2010 ANNUAL REPORT
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INTERDISCIPLINARY COLLABORATIONS MAKE AN IMPACT
CCB was born in September 2007 with the vision of unifying basic and translational research for the benefit of the cancer patient. Now, some 3 ½ years after, we are starting to see the fruits of the collaborations between cell biologists, geneticists, immunologists, informaticists and statisticians within the centre. As highlighted elsewhere in this report, CCB collaborations have already led to identification and functional characterization of a novel potential biomarker in colorectal cancer (Lind et al.,Oncogene, 2011), identification of novel regulators of cell division (Sagona et al., Nat. Cell Biol. 2010; Haglund et al., Curr.Biol., 2010), and analyses of clonal evolution of follicular lymphoma (Eide et al., Blood, 2010). These findings can potentially be exploited in future cancer diagnostics and therapies. From the above examples it appears that the joint efforts between scientists with different backgrounds lead to results that are more far-reaching than those that can be obtained by the indiviual groups alone. The added value of interdisciplinary collaborations is also illustrated by simple publication statistics. In 2008, the year after CCB was
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formed, CCB groups had no joint publications at all, reflecting that it takes some time from project start until papers are published. Next year the number had increased to four co-publications, and in 2010 there were as many as nine joint CCB publications, most of which were published in highly prestigious journals. The emerging picture is that collaborations across the disciplines yield a real improvement of scientific production and quality. In total, CCB published 63 papers in 2010, which is an all-time-high for the centre and an increase of 34% from 2009. As many as 16 of these papers were published in high-impact journals (impact factor over 9.0), which is twice the number obtained in 2009. The overall impression is that the research output of CCB is improving in terms of both volume and quality. This improvement can in part be attributed to the added value of interdisciplinary collaborations, but it is also clear that the recent move into a modern research building, and the acquisition of high-end instruments for imaging and mass sequencing also are starting to have a positive impact on CCB’s research.
This spring is going to be decisive for the future of CCB. Like seven other Centres of Excellence inaugurated in 2007, CCB is currently undergoing a mid-term review, whose outcome will decide whether CCB is going to receive Centre of Excellence funding from the Research Council for the second scheduled period, 2012-2017. Although we have not received the final decision of the evaluation when this report is being written, we feel very optimistic about the future. Not only has CCB experienced a marked increase in research collaborations, publication volume and publication quality, but the preliminary report we have received from the expert review panel is very encouraging. With this bright look to the future, we would like to thank all the members of CCB for their hard and dedicated work, true team spirit and enthusiasm. Together we have formed a viable centre for excellent cancer research that is making an impact internationally. Special congratulations go to Marianne Berg, Helge Brekke, Wanja Kildal and Yan Zhen, who successfully defended their PhDs in 2010. We would also like to thank our Board
tions that sponsor our research, including the Oslo University Hospital, the Research Council of Norway, the Norwegian Cancer Society, the Radium Hospital Legacy Foundation, the South-Eastern Norway Regional Health Authority, the National Institutes of Health, the European Science Foundation, the EU Marie-Curie Programme, and the European Research Council. Finally, in agreement with the recent Oslo University Hospital report for innovation strategy, CCB puts effort into developing research results into innovation through patent applications. We are grateful for the collaboration with Oslo Cancer Cluster and the TTO Inven2 in these matters. High-quality research is expensive, but we believe it is the best investment for the future.
and Scientific Advisory Board for their valuable advices and efforts to stimulate even further improvement of the centre. Our host institutions, the University of Oslo and the Oslo University Hospital, are thanked for excellent cooperations, and for
providing an infrastructure that is really state-ofthe-art. We would like to thank the many pathologists and clinicians at Oslo University Hospital for making our patient-oriented research possible. We are of course very grateful to those organiza-
Harald Stenmark
Ragnhild A. Lothe
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VISION AND AIMS
Cancer is a highly complex invasive cell disease, unique to small patient groups or even to single patients. Improvement of prognostics, diagnostics and therapy requires an integrated approach based on tumour parameters and patient specific properties. In Centre for Cancer Biomedicine more than 100 scientists from different disciplines share the common focus of disease understanding and development of affordable tools for early detection and tailored treatment of cancer.
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VISION AND AIMS
Vision
Scientific aims
The overall vision is to unite basic and translational research for the benefit of the cancer patient.
• Identify genetic, epigenetic and morphological characteristics of cancer cells • Develop and implement bioinformatic and biostatistical tools for handling complex data sets from canceromics and image analyses • Identify and characterize molecular and cellular mechanisms for regulation of cell growth, proliferation, survival, differentiation and motility – and link these to potential cancer biomarkers • Identify potential biomarkers for cancer, and validate their clinical utility
The efforts of the centre are aimed towards a better understanding of the complex dynamics of cancer evolution, a more accurate prediction of cancer prognosis and response to treatment and more powerful molecular based treatment.
TABLE OF CONTENTS
VISION AND AIMS
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HIGHLIGHTS
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RESEARCH GROUPS
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PRIZES AND AWARDS
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FORUMS
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COLLABORATIVE PROJECTS WITHIN CCB
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CCB TECHNOLOGY PLATFORMS
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DEGREES
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CCB SEMINARS
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VISITORS TO AND FROM CCB
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EDUCATIONAL ACTIVITIES
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PUBLICATIONS AND PRESENTATIONS
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COLLABORATIONS
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MEDIA
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ABOUT CCB
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CCB STAFF AND STUDENTS
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SPONSORS
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TABLE OF CONTENTS
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Two cover stories Figure from Harald Stenmark review article on the cover of FEBS Journal
Volume 277 Number 23 December 2010 pp.4805–4988
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HIGHLIGHTS
At the 2010 FEBS Congress in Gothenburg, Harald Stenmark from the Centre for Cancer Biomedicine and the Institute for Cancer Research was awarded the Sir Hans Krebs Medal (see also Prizes and Awards). The win+ ners of the Krebs med– al are invited to write a review article to be published in the FEBS Journal. An illustration from the Stenmark arHow a lipid mediates tumour suppression ticle - entitled “How a Engineering active siRNA therapeutics lipid mediates tumour suppression” - has been given the front page of the December 2010 issue. The review article describes how PtdIns3P causes tumor suppression by controlling endocytosis, autophagy and cytokinesis. Volume 277 Number 23 December 2010 | ISSN 1742-464X
www.febsjournal.org
The figure illustrates three processes controlled by PtdIns3P through its effector proteins (in red types), namely endocytosis, autophagy and cytokinesis (the final stage of cell division). Endocytosis contributes to tumour suppression through lysosomal degradation of activated growth factor receptors.
Rabenosyn-5, EEA1
Early endosome
HRS, EAP45
Multivesicular endosome
Lysosome
ER
Autophagosome Midbody ring
FYVE-CENT
WIPI2
DFCP1
Nucleus
Sir Hans Krebs Lecture Minireview Series
11/9/2010 1:47:03 PM
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HIGHLIGHTS
Autophagy contributes to tumour suppression by scavenging and degradation of damaged mitochondria and peroxisomes, which would otherwise cause DNA damage through production of toxic oxygen species. Correct cytokinesis has a tumour suppressor function by preventing the development of aneuploidy.
Article from Andreas Brech’s project group on the cover of Histochemistry and Cell Biology PhD student Catherine Sem Wegner and her colleagues in Andreas Brechs project group at CCB, Department of Biochemistry, Institute for Cancer Research, have published an article that was selected for the cover of Histochemistry and Cell Biology in January 2010. The article is a confocal and electron microscopic characterisation of giant endosomes that are induced by a mutant form of the small GTPase Rab5, a well-known regulator of endocytic trafficking. As shown on the cover, many of the giant endosomes contain numerous intraluminal vesicles and therefore correspond to multivesicular endosomes, which play a special role in downregulation of growth factor receptors.
Important CCB papers in 2010 Molecular mechanisms and clinical classification of B-cell lymphomas, published in Nature CCB, represented by Erlend Smeland’s group, is actively participating in a prestigious and highly successful large international collaborative project regarding molecular profiling of B cell lymphomas as one of four European groups (LLMPP, headed by Dr. Louis Staudt at NCI). These studies have led to a series of publications in top-ranked international journals. So far, the consortium has characterised several major subgroups of B-NHL by expression profiling. These studies led to the discovery of 3 previously unrecognised, distinct subgroups of diffuse large B cell lymphoma (DLBCL) - ABC, GCB and primary mediastinal B cell lymphoma (PMBL), which have distinct molecular profiles and different prognosis. A recent LLMPP study demonstrated that the adaptor protein CARD11, which is involved in NF-kB activation, is activated by somatic mutation in the coiled-coil region in a subset of ABC DLBCLs, and hence is a novel oncogene (Lenz et al, Science 2008). Recently, these findings have been extended, and it was demonstrated that ABCs are dependent on chronic B cell receptor signalling and demonstrated frequent somatic mutations in the BCR associated molecules CD79a and b (Davis et al, Nature, 2010). B cell receptor signalling can be responsible for NF-kB activation in many ABC DLBCLs, which lack activating mutations in CARD11 (the latter are only observed in 10% of ABCs, while practically all ABCs demonstrate NF-kB activation). The
LLMPP consortium is now applying for new NIH grants to support a development and validation of diagnostic tools based on the obtained results in the project.
Review Articles about Possibilities and Challenges for using Nanoparticles in Medicine During recent years there has been much interest in using nanoparticles for in vitro studies as well as for drug delivery and as contrast agents in animals and humans. In nanomedicine there is a need for combining knowledge in cell biology with experience from clinical studies. Sandvig’s group has published several high impact articles in the field of nanomedicine during the last couple of years.
Much of the discussion is also relevant for other type of nanoparticles and for their therapeutic use. Another review article, which is in press in Nano Today (impact 13.3), describes the present knowledge and need for future in vitro studies. The possibilities, challenges and pitfalls in studies of nanoparticles are discussed. These review articles are the result of the combined expertice acquired from our own research on nanoparticles, our long experience in the field of endocytosis and intracellular transport and new competence in the group regarding in vivo metabolism, distribution and excretion of nanoparticles.
In the December issue of Nanomedicine, the Sandvig group has published a review article about in vivo use of nanoparticles. The main focus is on metalbased nanoparticles for in vivo imaging and requirements for bringing such particles from in vitro studies and imaging in animals into common clinical use.
HIGHLIGHTS
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Identification of a high risk group among patients with malignant nerve sheath tumors
Genomic changes in chromosomes 10, 16, and X in malignant peripheral nerve sheath tumors identify a high-risk patient group.Brekke HR, Ribeiro FR, Kolberg M, Agesen TH, Lind GE, Eknaes M, Hall KS, Bjerkehagen B, van den Berg E, Teixeira MR, Mandahl N, Smeland S, Mertens F, Skotheim RI, Lothe RA. J Clin Oncol. 2010 28:1573-82.
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HIGHLIGHTS
Lifetme distributon of clathrin-coated pits ± Shiga toxin 50 45 Number of AP2 spots
In an interdisciplinary multicentre study, including University of Lund, Portuguese Oncology Institute, University Hospital of Groningen and Oslo University Hospital, the Lothe group identified a high risk group among patients with malignant nerve sheath tumors (MPNST) In an unbiased manner the DNA copy number variation throughout the tumor genome was examined for suitability as surrogate markers for survival. Variations at each of three chromosomal sites in the tumor identified a high risk group with only 11% 10 year disease specific survival. In contrast, the patients without these any of these tumor changes had 74% 10 year survival. Multivariate analyses including NF1 status, tumor location, size, grade, sex, complete remission, and initial metastatic status showed that the genomic high-risk group was the most significant predictor of poor survival. Several genes whose expression was affected by the DNA copy number aberrations were identified.
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Disease specific survival for patients with MPNST based on selected genetic variables.
Crosstalk between Clathrindependent Endocytosis and a Lipidbinding Ligand The article by Utskarpen et al. PLoS ONE (2010) shows that a lipid-binding ligand signals to change the clathrin-dependent pathway through Syk kinase. That signalling through a lipid such as Gb3, a neutral sphingolipid of importance for cancer metastasis, can affect endocytic uptake by increasing the number and life-time of clathrin-coated pits was shown for the first time in this article. That crosslinking of glycosphingolipids can have such effects further emphasizes their importance for cellular behaviour and opens for more detailed studies of the role of different sphingolipid classes and species. The article in PLoS ONE caught the attention of editors in the journal Lab Times, and an article presenting the research activities of our group is in press.
Shiga toxin
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Biomarkers for urological cancers In a collaborative study between the laboratory of Manuel R Teixeira, a guest professor in CCB, and the lab of Ragnhild Lothe we have over time identified biomarkers with relevance for urological cancers. Recent findings for bladder cancer detection have particular clinical interest. Identification of biomarker panel that predict bladder cancer from urine analysis. Vera Costa, a PhD student of Carmen Jeronimo, spent time in the project group of Guro E. Lind to learn and apply the methodological approach Lind has reported for identification of epigenetic markers in cancer combining epigenetic drug treatment of in vitro models with gene expression data of primary cancers (Lind et al., Cell Oncol 2006). Costa applied this on the three main urological cancers, prostate cancer, kidney cancer and bladder cancer.
Translational relevance
Our study identified a 3- gene panel of epigentic biomarkers, GDF15, TMEF2 and VIM, that accurately detect bladder cancer (BlCa) in urine sediments and discriminate it from prostate cancer and renal epithelial tumors. This panel might be easily applied for routine screening of BlCa in voided urine samples.
Receiver operator curve in BlCa urines for individual markers (A) and for the best combination of three genes (B). Three epigenetic biomarkers, GDF15, TMEFF2, and VIM, accurately predict bladder cancer from DNA-based analyses of urine samples. Costa VL, Henrique R, Danielsen SA, Duarte-Pereira S, Eknaes M, Skotheim RI, Rodrigues A, Magalhães JS, Oliveira J, Lothe RA, Teixeira MR, Jerónimo C, Lind GE. Clin Cancer Res 2010 16:5842-51.
HIGHLIGHTS
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Integrin degradation and cell migration One of the hallmarks of cancer cells is their ability to invade tissues outside the site of the initial tumour. In cancer research there is therefore a lot of interest in mechanisms that regulate the ability of cells to move. Integrin molecules are membrane proteins that mediate the traction between cells and the extracellular matrix, and it is well known that their internalisation and recycling are required for cell migration. Now, CCB PhD student Viola Lobert and her co-workers have made the unexpected observation that degradation of integrin molecules is important for cell migration. This degradation is induced by a component of the extracellular matrix, which triggers ubiquitination of the integrin molecules. Ubiquitinated integrins are recognised by the so-called endosomal sorting complex required for transport (ESCRT), which sorts the integrins to lysosomes for degradation (Lobert et al., Developmental Cell, 2010). This mechanism ensures that internalised integrin molecules that contain portions of extracellular matrix are not recycled to the plasma membrane where they would otherwise have made dysfunctional adhesion sites. This project was a collaboration between two CCB groups, and the paper was dedicated a “Highlight” in Nature Reviews in Molecular Cell Biology and an editorial comment on the Nature Cell Migration Gateway.
Figure legend: Integrin trafficking requires the ESCRT machinery. Here, integrin (in red) accumulates at early endosomes (labeled by EEA1, in blue) together with ubiquitin (green) upon depletion of the ESCRT machinery. Lobert VH, Brech A, Pedersen NM, Wesche J, Oppelt A, Malerød L and Stenmark H (2010). Ubiquitination of α5β1 integrin controls fibroblast migration through lysosomal degradation of fibronectin-integrin complexes. Dev. Cell 19: 148-159.
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HIGHLIGHTS
PhD thesis: ”Genomics of colorectal carcinomas from young and elderly patients” Marianne Berg PhD 2010, The Faculty of Medicine, University of Oslo The genetic constitution of a patient is expected to contribute to the timing of tumor initiation, and thus the patient’s age at onset. In this work, tumor biopsies from patients with CRC at young age (70 years). The aim was to identify molecular differences in colorectal cancer development related to age at disease onset. The critical cancer gene set, KRASBRAF-PIK3CA-PTEN-TP53, was investigated for sequence alterations and large rearrangements in all tumors. Interestingly in view of EGFR based antibody therapy for CRC, mutations in the PTEN were present as sole mutations only in tumors (16%) from the young individuals. If validated, this suggests that mutation status of KRAS and BRAF alone is not a sufficient companion diagnostic test for EGFR therapy among young patients (Berg et al., 2010 PLoSOne 5(11):e13978). Overall a lower gene mutation index was found for tumors from young compared to elderly patients. In contrast, the
highest genomic complexity, assessed by arrayCGH, was identified for tumors from young individuals (Berg et al., 2010 Mol Cancer 9:100). Integrative analyses of the copy number variation and gene expression changes comparing the two tumor groups identified 15 genomic loci with preferential copy number changes in the tumors from young individuals and 107 genes with expression levels corresponding to these copy number changes. From the transcriptome data set alone 22 genes had elevated expression levels and 9 had reduced levels in tumors from young compared to elderly patients. An elevated immune content within the early onset group was observed from the differentially expressed genes (Ågesen, Berg et al., submitted Genes Immunity). Graphics of patients with hypothesized response to EGFR-targeted therapy. Mutation percentages indicated in two age groups: 70 ye. “Quadruple negatives” are potential responders to EGFR therapy.
DNA sequence profiles of the colorectal cancer critical gene set KRAS-BRAF-PIK3CA-PTEN-TP53 related to age at disease onset. Berg M, Danielsen SA, Ahlquist T, Merok MA, Ågesen TH, Vatn MH, Mala T, Sjo OH, Bakka A, Moberg I, Fetveit T, Mathisen Ø, Husby A, Sandvik O, Nesbakken A, Thiis-Evensen E, Lothe RA. PLoS One. 2010 5(11):e13978. Distinct high resolution genome profiles of early onset and late onset colorectal cancer integrated with gene expression data identify candidate susceptibility loci. Berg M, Agesen TH, Thiis-Evensen E; INFAC-study group, Merok MA, Teixeira MR, Vatn MH, Nesbakken A, Skotheim RI, Lothe RA. Mol Cancer. 2010, 9:100. CLC and IFNAR1 are differentially expressed and a global immunity score is distinct between early and late onset colorectal cancer Ågesen TH, Berg M, Clancy T, Thiis-Evensen E, Cekaite L, Lind GE, Nesland JM, Bakka A, Mala T, Hauss HJ, Fetveit T, Vatn MH, Hovig E, Nesbakken A, Lothe RA, Skotheim RI. Submitted Genes and Immunity.
HIGHLIGHTS
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RESEARCH GROUPS
Harald Stenmark group
Intracellular communication Main interests The main interest of the group is to understand how a membrane lipid, phosphatidylinositol 3-phosphate (PtdIns3P), coordinates cellular activities to mediate tumour suppression. A key discovery that paved the way for most of the group’s current activitites was the identification of the conserved FYVE domain, and the demonstration that this domain binds PtdIns3P (1).
About Our group has more than 20 members from 10 nations. We use advanced microscopy methods such as confocal and electron microscopy in combination with molecular biology approaches to study how normal cells develop into cancer cells. Most of the group members work with various cultured cell lines derived from normal tissues and cancers whereas others use the fruit fly Drosophila melanogaster as a convenient model organism. In addition to collaborations with leading international laboratories, the group works closely together with translational cancer researchers and biostatisticians within CCB.
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RESEARCH GROUPS
Studies of PtdIns3P have led to our interest in the following cellular processes: • Endosomal protein sorting as a tumour suppressor mechanism • Autophagy in development and tumour suppression • Spatial control of receptor signalling • Membrane dynamics of cell division
Projects
The group has 4 project groups: • “Unit for cellular electron microscopy” (headed by Andreas Brech) • “Cytokinesis in development and carcinogenesis” (headed by Kaisa Haglund) • “Phosphatidylinositol signalling & disease” (headed by Tor Erik Rusten) • “Membrane-associated protein dynamics in cell division” (headed by Camilla Raiborg and Hilde Abrahamsen)
Recent discoveries
• The FYVE domain protein EEA1 is a Rab5 effector in endosomal fusion (2) • PtdIns3P is highly enriched on endosome membranes (3) • The FYVE domain protein Hrs mediates sorting of ubiquitinated receptors for lysosomal degradation (4) • Hrs recruits the ESCRT machinery to endosomes in order to mediate receptor sorting into the intraluminal vesicles of multivesicular endosomes (5) • Class I PI 3-kinase negatively regulates autophagy in Drosophila, autophagy is turned on during development by downregulation of PI 3-kinase activity (6). • The ESCRT machinery is required for completion of autophagy (7) • Autophagic degradation of a caspase inhibitor is a mechanism to activate programmed cell death (8). • The ESCRT machinery mediates degradation of ubiquitinated integrin molecules, and this is required for cell migration (9). • PtdIns3P is required for correct cytokinesis, and the FYVE domain protein FYVE-CENT is a key regulator of this process (10). • Cindr/CIN85 is a key regulator of complete and incomplete cytokinesis in Drosophila (11).
Selected publications
1. Gaullier J-M, Simonsen A, D’Arrigo A, Bremnes B, Aasland R and Stenmark H (1998) FYVE fingers bind PtdIns(3)P. Nature 394: 432-433. 2. Simonsen A, Lippé R, Christoforidis S, Gaullier J-M, Brech A, Callaghan JM, Toh B-H, Murphy C, Zerial M and Stenmark H (1998) EEA1 links PI(3)K function to Rab5 regulation of endosome fusion. Nature 394: 494-498. 3. Gillooly DJ, Morrow, IC, Lindsay M, Gould R, Bryant, NJ, Gaullier J-M, Parton RG and Stenmark H (2000) Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells. EMBO J. 19: 4577-4588. 4. Raiborg C, Bache KG, Gillooly DJ, Madshus IH, Stang E and Stenmark H (2002) Hrs sorts ubiquitinated proteins into clathrin-coated microdomains of early endosomes. Nat. Cell Biol. 4: 394-398. 5. Bache KG, Brech A, Mehlum A and Stenmark H (2003). Hrs regulates multivesicular body formation via ESCRT recruitment to endosomes. J.Cell Biol. 162: 435-442. 6. Rusten TE, Lindmo K, Juhasz G, Sass M, Seglen P, Brech A and Stenmark H (2004). Programmed autophagy in the Drosophila fat body is induced by ecdysone through regulation of the PI3K pathway. Dev.Cell 7: 179192. 7. Rusten TE, Vaccari T, Lindmo K, Rodahl LMW, Nezis, IP, Sem-Jacobsen C, Wendler F, Vincent J-P, Brech A, Bilder D and Stenmark H (2007). ESCRTs and Fab1 regulate distinct steps of autophagy. Curr. Biol. 17: 1817-1825.
8. Nezis IP, Shravage BP, Lamark T, Rusten TE, Sagona AP, Bjørkøy G, Johansen T, Brech A, Baehrecke E and Stenmark H (2010). Autophagic degradation of inhibitor of apoptosis dBruce triggers cell death during late oogenesis in Drosophila. J. Cell Biol. 190: 523-531. 9. Lobert VH, Brech A, Pedersen NM, Wesche J, Oppelt A, Malerød L and Stenmark H (2010). Ubiquitination of α5β1 integrin controls fibroblast migration through lysosomal degradation of fibronectin-integrin complexes. Dev. Cell 19: 148-159. 10. Sagona AP, Nezis IP, Pedersen NM, Liestøl K, Poulton J, Rusten TE, Skotheim RI, Raiborg C and Stenmark H (2010). PtdIns3P controls cytokinesis via KIF13A-mediated recruitment of FYVE-CENT to the midbody. Nat.Cell Biol. 12: 361-372. 11. Haglund K, Nezis IP, Lemus D, Grabbe C, Wesche J, Liestøl K, Dikic I, Palmer R and Stenmark H (2010). Cindr interacts with anillin to control cytokinesis in Drosophila melanogaster. Curr.Biol. 20: 944-950.
RESEARCH GROUPS
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RESEARCH GROUPS
Kirsten Sandvig group
Intracellular transport
About Sandvig’s group is interested in the mechanisms of endocytosis, intracellular transport and secretion. Uptake of receptors and ligands and correct intracellular sorting of endocytosed molecules are crucial for maintenance of a normal differentiated phenotype. In some of our studies we are using protein toxins which are well established as markers for studies of membrane traffic, and which can be used as agents in cancer diagnosis and therapy. Our expertice is also applied to investigate uptake of nanoparticles and to characterize release of exosomes from prostate cancer cells with the goal of detecting lipid and protein biomarkers.
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RESEARCH GROUPS
These projects aim at increasing our knowledge about intracellular transport and biomarkers in order to provide a rational basis for diagnosis, treatment and prevention of disease.
on intracellular sorting. Several international collaborations are ongoing to increase the impact of our projects.
Challenges
Characterization of intracellular transport
Cancer is associated with errors in trafficking and signaling, and differences in expression of surface molecules and transport/signaling between normal and cancer cells can be exploited to detect and kill tumor cells. The Shiga toxin receptor is expressed by a number of human tumors, and Shiga toxin can be used for in vivo tumor targeting and imaging. A number of the protein toxins are of interest also in connection with targeted drug delivery of toxin conjugates. To construct active toxin conjugates, one needs to know which part of the toxin molecule to include, and whether targeting to a specific intracellular compartment is required. For this purpose, knowledge about the relationship between toxin structure and function and the mechanisms of intracellular sorting is essential. Importantly, the toxins have proven valuable to reveal and characterize pathways in cells. By using a combination of morphological, biochemical and molecular biological approaches, we are investigating the various aspects of intracellular transport. We are characterizing the impact of protein complexes, kinases and specific membrane lipids
Projects Toxins are in some of our studies used to discover and characterize intracellular pathways. A main focus is to investigate cellular transport mechanisms in normal and cancer cells to provide a scientific basis for cancer diagnosis and therapy. Entry of nanoparticles into cells This project aims at gaining more knowledge about endocytic mechanisms and intracellular pathways followed by various nanoparticles in cells, and the role of size and composition of nanoparticles for the compartments reached and for their clearance from cells. Such knowledge is essential for exploiting nanoparticles in medicine. Membrane transport in prostate cancer cells: Release of microvesicles One principal objective of this project is to obtain knowledge about vesicular transport in prostate cancer cells. This will increase our understanding
of prostate carcinogenesis. Both proteomics and lipidomics of exosomes are run with the goal of obtaining biomarkers.
Recent achievements Some recent findings/articles published by our group in 2010-: Shiga toxin increases formation of clathrin coated pits through Syk kinase (Utskarpen et al., PLoS ONE 5 (2010), e10944. Shiga toxin binds to the neutral glycosphingolipid Gb3 which is mainly expressed on cancer cells, and we have published a review on the use of Shiga toxin in targeted cancer therapy and imaging: Engedal et al., Microbial. Biotechnol. 4 (2011), 32-46. We have studied the role of flotillin on endocytosis and retrograde transport: Pust et al., PLoS ONE 5 (2010), e8844, and we have used our knowledge about endocytic pathways to investigate entry of another toxin, Clostridium botulinum C2 toxin (Pust et al. Cell. Microbiol. 12 (2010) 1809-1820). The importance of Toll-like receptor 4 in Shiga binding was published by Torgersen et al. in FEMS Immunol. & Med. Microbiol. 61 (2011) 63-75. A side-project in collaboration with another group, dealing with protein C was also published last year (Tjeldhorn et al. BMC Cell Biol. 11 (2010) 67). Other reviews published during the year, on toxins and nano-
particles include: Skotland et al. Nanomedicine 6 (2010) 730-737; Iversen et al. Nano Today, In Press; Sandvig et al., FEBS Letters 584 (2010) 2626-2634; Sandvig et al., Toxicon 56 (2010) 1181-1185; and Torgersen et al., The Open Toxinology Journal 3 (2010) 2-12.
Confocal laser scanning microscopy image showing cultured HEp-2 cells where the B-subunit of Shiga toxin (green colour) has been internalized and transported to the Golgi apparatus (red colour). Cell nuclei are stained in blue. Scale bar: 10 µm.
RESEARCH GROUPS
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RESEARCH GROUPS
Antoni Wiedlocha group
Protein internalisation and signaling
cells including culturing of putative cancer stem cells. The interest of FGF-induced signaling as a promising target for cancer therapy has systematically been increasing. We have been focusing on (i) how FGFs/FGFRs signaling can contribute to development of malignant phenotype of different types of cancer when it is deregulated and (ii) finding new potential molecular targets in FGFregulated processes that would be beneficial in cancer therapy.
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FGF1 and 2 may, in addition, be translocated from the extracellular space into the cytosol and nucleus. Nuclear FGF1 and 2 have been reported to be able to regulate processes such as rRNA synthesis and cell growth as well as metastasis formation in certain tumors. We would like to understand the molecular mechanism of the intracrine signaling of the growth factors by identification of new intracellular FGF1 and 2 binding proteins and how the translocation process of the growth factors occurs and is regulated.
About
Challenges
Fibroblast growth factors (FGFs) and FGF receptors (FGFRs) exert a powerful combination of biological effects. Therefore imbalances in FGFs/ FGFRs signaling contribute to the essential hallmarks of cancer. The growth factors are frequently and abundantly expressed in various tumors and are recognized as key mediators of the epithelialmesenchymal transition, tumor cell survival, migration/metastasing and neoangiogenesis as well as stress-induced agents causing rescue of tumor tissues during/after therapy. On the other hand in some circumstances the FGF regulated signaling network contributes to tumor suppression. Moreover, FGF2 is the most common growth factor used to expand embryonic and tissue-specific stem
Transphosphorylation of tyrosine residues in the kinase domain of FGFRs leads to activation of different signaling cascades. Our recently obtained data revealed that upon FGFR1 activation the receptor is directly phosphorylated on C-terminally located serine by activated MAP kinases Erk1 and 2 resulting in decreased tyrosine kinase activity of the receptor. This serine phosphorylation provides a novel downregulation mechanism of FGF/FGFR signaling.
We would like to clarify the involvement of these mechanisms in development of malignant phenotype.
Endocytosis, sorting and degradation of activated FGFRs is another important mechanism to down-regulate activity of the receptors which can contribute to tumor suppression. Deregulation of these processes might be tumor promoting.
• Identification of intracellular proteins interacting with FGF1 and 2.
RESEARCH GROUPS
Projects • Activation and termination of FGF/FGFR induced signaling. • Endocytosis, sorting and intracellular transport of FGF1 and FGFRs.
• Mechanisms of FGF-induced cancer cell migration.
Recent discoveries The contribution of nuclear FGF1 in regulation of stimulation of DNA synthesis and the cell growth was described by us for the first time (Wiedlocha et al., Cell 1994; Wiedlocha et al., Mol. Cell. Biol.1996). This led us into studies of entry-mechanism of FGF1 and 2 into cells (Malecki et al., EMBO J. 2002; Malecki et al., Mol. Biol. Cell 2004; Wesche et al., J. Biol. Chem. 2006; Sørensen et al., J. Cell Sci. 2006) and regulation of nuclear import and export of translocated exogenous FGF1 (Wiedlocha et al., Mol. Biol. Cell 2005). Continuing the studies we identified a second nuclear localization sequence (NLS) in FGF1 (Wesche et al., Biochemistry 2005) as well as a functional and transplantable FGF1 nuclear export sequence (NES) (Nilsen et al., J. Biol. Chem. 2007). In this paper we also showed that FGF1 binds to exportin-1 and RanGTP, (to form the nuclear export complex), in a FGF1 phosphorylation dependent manner. The FGF1 NES was found to be situated along a bstrand, which has not been reported before. The very recent discoveries cover: demonstration that translocation of FGF1 into cells requires active p38 MAPK. The requirement for p38 MAPK-mediated phosphorylation of FGFR1 at ser777, demonstrating for the first time a specific role for serine phosphorylation of FGFR1 (Sørensen et al., Mol. Cell. Biol. 2008). Discovery that indirubin-3’-monoxime is an efficient and specific inhibitor of the tyrosine kinase FGFR1 and it may have clinical implication
(Zhen et al., Oncogene 2007). Demonstration that ubiquitination is important for sorting FGFR1 and 4 but not for their endocytosis (Haugsten et al., J. Cell Sci. 2005; Haugsten et al., Mol. Biol. Cell. 2008). Demonstration that FGF1 is able to deliver heterologous polypeptides into the cytosol and nucleus of mammalian cells (Zakrzewska et al., Biochemistry 2009). Discovery that the main role of heparin/heparans is to protect FGF1 against heat and proteases under physiological conditions and that it is not required to form functional FGF/FGFR complex (Zakrzewska et al., J. Mol. Biol. 2005; Zakrzewska et al., J. Biol. Chem. 2009). Discovery that the translocation of FGF1 into cells is a periodic event that occurs with 24 h intervals (Zakrzewska et al., Exp. Cell Res. 2011). Demonstration that a fusion protein containing permanently active tyrosine kinase domain of FGFR1, that is the driver of malignancy in KG-1a human leukemic cells, is a HSP90 addicted signaling oncoprotein and that this provides a rationale for the therapeutic use of HSP90 small molecule inhibitors in myeloid leukemias that contain FGFR fusion oncoproteins (Yixin et al., manuscript submitted). Also recently, in collaboration with Institute of Biochemistry, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland, we identified several new FGF1 and 2 intracellular binding partners, which are currently under investigation.
RESEARCH GROUPS
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Erlend Smeland group
Translational research in malignant lymphoma and has significant international collaboration. We are involved in a broad international collaboration headed by L. Staudt at NCI as one of eight centres (The Leukemia and Lymphoma Molecular Profiling Project, Smeland is site-PI for this project).
Challenges
About Smelands group studies B-cell lymphoma, which represents a heterogeneous group of diseases with many subgroups. The group has a strong translational focus and a close collaboration with the lymphoma program in our Hospital. Several of our projects are connected to ongoing clinical trials and we analyze biopsy samples using a broad spectrum of methods and correlate findings with clinical data. We use high throughput analysis of gene expression, and combine this with identification of genomic, epigenetic and signaling alterations. In addition, the lymphoma specific changes in genes or gene expression are followed up by basic cell biology research, using B cell lymphoma cell lines as models. The group has established collaboration with several other groups in CCB, 18
RESEARCH GROUPS
Malignant lymphomas represent a diagnostic and therapeutic challenge. The different subgroups differ highly in clinical course, of which some still are incurable in vast majority of cases (mantle cell lymphoma and follicular lymphoma). New therapeutic approaches, in particular monoclonal antibodies (Rituximab, targeting CD20) in combination with chemotherapy, have highly improved the outcome. Recently, a large number of targeted therapies (kinase inhibitors, proteasome inhibitors, and epigenetic drugs) have entered clinical trials, but how efficient they are in the various B-cell lymphoma subgroups, and their exact mechanism of action still needs to be precisely determined.
Aim The aim of our research group is to improve the understanding of malignant B cell lymphoma in order to develop new diagnostic tools, new prognostic markers and to improve treatment of this group of diseases.
Projects • Identification of signaling profiles with association to clinical outcome in mantle cell lymphoma and small lymphocytic lymphoma
• CGH array and expression profiling of serial biopsies of follicular lymphoma • Effects of Bone Morphogenetic Proteins (BMPs)/ TGF-β in normal and malignant B cells • The role of ZFYVE9 and ZFYVE16 in signaling and trafficking of cytokine receptors. • Immunohistochemical analysis of signaling pathways and infiltrating cells during progression and transformation of follicular lymphoma using TMAs • Epigenetic mechanisms in the development of malignant lymphoma • Studies of SNPs in immune response genes and genes involved in drug metabolism – correlation to clinical parameters in malignant lymphoma • Molecular profiling of lymphomas (Lymphoma and leukemia molecular profiling project, LLMPP). International collaborative study headed from NCI, E: Smeland is site-PI.
Recent achievements The activated B cell (ABC) subtype of diffuse large B cell lymphoma (DLBCL) has a constitutively active NF-kB pathway. In 10% of the ABC DLBCL patients, this could be explained by somatic mutations in the adaptor protein CARD11 (Lenz et al, Science 2008). Recently, we have extended these findings and demonstrated that ABCs are dependent on chronic B cell receptor signalling (BCR) and demonstrated frequent somatic mutations in the BCR associated molecules CD79a and b (Davis R et al, Nature, 2010). This implicates BCR signalling in the pathogenesis of ABC DLBCL and
suggests that antigenic stimulation participates during disease development. In a collaborative study conducted at Stanford University, we recently showed that BCR signaling is also crucial for pathogenesis of follicular lymphoma, an indolent disease that often transforms to DLBCL. Using phospho-protein specific flow cytometry to identify signaling profiles with prognostic potential, we found a distinct lymphoma subpopulation characterized by impaired B cell antigen receptor signaling (Irish et al, P.N.A.S 2010). The expansion of this intra-tumor subset, termed lymphoma negative prognostic (LNP) cells, correlated with disease progression and increased following therapy, suggesting these cells contribute to chemotherapy resistant disease. Resistance to negative regulators, including TGF-β, can further influence pathogenesis of B cell lymphoma. We found that
resistant TGF-β cell lines had constitutive activation of the Akt/ERK1/2 and mTOR pathway, whereas sensitive cell lines had constitutive active p-38 (Bakkebø et al., BMC immunol, 2010). We have also studied serial biopsies from 44 patients with follicular lymphoma with genome-wide CGH arrays. Gains involving chromosome 2, 3q and 5 were exclusively present in FL biopsies from cases with higher grade transformation and associated with inferior survival (Eide et al, Blood, 2010). Furthermore, the initial samples frequently harboured gains or losses that were absent in relapse samples, indicating that tumour cell clones at relapse were not direct descendants of initially dominating clones, thus supporting the hypothesis of common progenitor cells in FL.
RESEARCH GROUPS
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Statistical Analysis Unit headed by Knut Liestøl
Data analysis, Statistical methods development
within CCB projects but additionally by addressing more specific statistical questions arising in CCB. • Developing methods and software for relevant biostatistical problems, typically motivated by problems originating from concrete biomedical investigations.
Challenges About The statistical analysis unit is part of the Biomedical research group (Bio) at the Department of Informatics, University of Oslo. The research activity in the Bio group is directed towards methods development and applications of biostatistics, bioinformatics and computational science in the medical sciences, and in particular in medical genomics.
Aims The statistical analysis unit in CCB aims at • Supporting the activity of the CCB groups by providing data analysis, primarily through working
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The statistical analysis group has its main activity within analysis of data from high throughput technologies in genetics and molecular biology. While rich in information, the complexity of these large data sets makes extraction of information a true challenge. As opposed to the typical situation in classical statistics, high throughput technologies require methods adapted to (relatively) few samples and high numbers of observations on each sample. The group’s philosophy is to work in close interaction with the biomedical research groups also to obtain own competence in the application areas. Typically, projects in the group initially focus on a concrete biomedical problem; we then try to solve
the statistical challenges in a broader context and finally develop adapted software tools. On the methodological side, our focus has been on problems from survival analysis, nonparametric/nonlinear statistical modelling, and how to handle many covariates in regression.
Recent work One main area of work has been the analysis of copy number alterations. This includes both applications together with other CCB groups and development of methods and software. On the software side we are now finalizing a system for fast simultaneous estimation from several samples; the system is written in R and adapted to the Bioconductor requirements. In 2010 applications included publication in Blood in collaboration with Smeland’s group. Another main effort has been the analysis of siRNA screens. In 2010 we contributed to a publication from Stenmark’s group in Nature Cell Biology, and three other subprojects are approaching publication. Additionally, we have in 2010 contributed to several projects using modern regression methods on RNA expression data, mainly in collaboration with the groups of Lothe and Smeland.
Quantification and statistical analysis of microscopy data.
RESEARCH GROUPS
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Håvard Danielsen group
Large scale genomic instability
About Cancer arises from a single or a few transformed cells, and by the time a cancer is diagnosed, it comprises billions of cells carrying multiple, and mostly different, DNA- and chromatin abnormalities. Today’s powerful technologies are enabling these changes to the genome to be catalogued in detail. If these billions of cells in a given tumour were carrying a specific aberration that initiated malignant proliferation of the single or few transformed cells, one would expect that the initiator would be easily detected. If indeed a given cancer type is characterised by one or a few specific aberrations, one would expect that such “true oncogenes” would also be easily detected. Evidence is instead accumulating indicating a close link be-
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tween genomic instability and cancer initiation and progression. Neoplastic cells typically possess numerous genomic lesions, which may include sequence alterations and/or gross structural abnormalities in one or more chromosomes. Furthermore karyotypic alterations, including whole chromosome loss or gain, ploidy changes (aneuploidy and polyploidy) and a variety of chromosome aberrations are common in tumour cells. The loss of genomic stability appears to be a key molecular and pathogenetic step that occurs early in the tumorigenesis process and serves to create a permissive environment for the occurrence of alterations in tumour suppressor genes and oncogenes. Danielsens group are developing high throughput methods for detection and characterisation of large-scale genomic instability (chromatin structure and ploidy), based on high-resolution digital microscopy and advanced image analysis. They are studying archival material at the time of diagnosis from patients with proper clinical follow-up and known prognosis, in large series of colorectal, breast, prostate and gynaecological cancers. In parallel, karyotyping, CGH and FISH are used to search for specific genomic changes in the same
tumours, and attempts are made to establish the relationship between specific genomic changes and chromatin structure. Sverre Heim’s research on the chromosome aberrations of cancer has from 2010 onward been included as part of the CCB. Their research proceeds along three axes: 1. Characterization of ovarian cancer acquired genomic abnormalities. 2. Characterization of the genomic abnormalities acquired by brain tumors. 3. Detection of novel fusion genes brought about by new cancer-specific chromosomal translocations. In all three areas, they initially determine the tumor karyotype by cytogenetic means, then molecular techniques are relied upon to understand the acquired abnormality of interest in increasing detail.
Specific aims The main aims are to complete the methodology and system that detects and classifies large scale genomic instability in tumours by analysing nuclei in routine histological biopsies, and to use this to analyse the large series of common cancers and
define more precise prognostic markers for these cancer types. Results from different cancer types, as well as from different methods of instability indicators (DNA ploidy, Nucleotyping, FISH, CGH, Karyotyping), are compared and analysed in an attempt to obtain new knowledge about the mechanistic and pathobiology of large scale genomic instability. Detection and classification of genomic instability may be a key disease biomarker for cancer, and knowledge of the biochemical mechanisms behind it is likely to identify the next set of key therapeutic targets.
Recent discoveries and achievements Methods and systems for high throughput analysis of chromatin structure and DNA ploidy in nuclei from routine biopsies are developed, and DNA ploidy have been shown to have independent prognostic power in Gleason 7 prostate cancers (Pretorius et al, Cell Oncol.31(4):251-9,2009), in uterine sarcomas (Kildal et al, Ann Oncol, 20(6);1037-41,2009), and most recently in colon cancer (in preparation). Our high throughput meth-
od for analysing tissue micro arrays (TMA) based on virtual microscopy (Brekke et al, Neuro Oncol. 11(5):514-28,2009 and Arnoldussen et al, Cancer Res. 68(22)_9255-64, 2008) is now complemented with new software for automatic quantification of expression (in prep). A new and enhanced version of the DNA Ploidy system has been finalised, and development of methods for high throughput automatic segmentation and classification of nuclei in histological sections have been completed (patents pending). Microtracker, a new concept for cell-by-cell comparison of results from different methods have been patented (UK patent 2010)
Projects • Nucleotyping as a prognostic marker in prostate cancer and Colorectal cancers • 3-D analysis of chromatin structure • Cell-by-cell comparison of FISH, IHC and Nucleotyping in 3-D reconstructions of nuclei from routine histological biopsies (Microtracker)
RESEARCH GROUPS
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Ragnhild A. Lothe group
Translational research of colorectal cancer
We are also involved in studies of other solid tumours, in particular studies on urological cancers, and have initiated and contribute in several collaborative projects within the CCB.
Aims About Our group studies colorectal cancer with a strong translational research focus. Understanding molecular mechanisms underlying human tumour development is essential to improve the diagnosis and treatment of the cancer patient. To gain knowledge of the complex dynamics of these abnormal processes our group combines patientoriented and detailed biology research using human biobanks and in vitro models. Technologies in genetics, epigenetics, bioinformatics and cell biology are employed in our laboratory. We handle in-lab various microarray platforms, including an own designed universal fusion gene array, deepsequencing, and confocal microscopy.
The underlying biology of colorectal cancer and the many, yet unresolved, clinical challenges related to this disease are the crux of our translational research activities. The researchers at department of Cancer Prevention aim to identify and functionally and clinically validate new biomarkers for improved diagnostics and therapy of this malignancy.
Challenges Colorectal cancer is the second most frequent cause for cancer deaths in the Western world and the incidence in Norway alone is more than 3500 per year. The golden standard for early detection is colonoscopy; the invasiveness of the method and costs show the need for improved non-invasive tests for discovery of precursor lesions and of ear-
ly cancer stages. Furthermore, the present clinical staging is crude and more precise molecular tools are asked for to better select those that will benefit from adjuvant treatment with the intention to cure and leave those who will be cured by surgery alone. There is an urgent need for biomarkers with predictive power and to identify those that can be used for targeted therapy.
Projects • Genetics of young at onset colorectal cancer • Biomarkers for early detection of colorectal cancer and development of non-invasive tests • Predictive and prognostic signatures for substaging of colorectal cancer. • Deep sequencing of stage II tumors selected by a novel prognostic gene signature • Molecular phenotypes of colorectal cancer • Genomics and exon level transcriptomics of colorectal cancer
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• miRNA in development of colorectal cancer • Urological cancer Tumor stem cells and germ cell tumors Genomics of prostate cancer • Malignant peripheral nerve sheath tumors Prognostic markers, druggable targets • Biomarker validation in large clinical series. Tissue microarrays constructed and in use for each disease type we study The Lothe group includes one project group: Epigenetics in colorectal cancer and other solid tumors, headed by Guro E. Lind. Two other research groups in Department of Cancer Prevention are members of CCB: The Cell Biology group, headed by Edgar Rivedal, studies disease mechanisms with focus on protein degradation and intercellular communication
through the connexin protein family in interplay with cell signalling. The group works integrated with some of the colorectal cancer projects. The Genome Biology group headed by Rolf I. Skotheim, studies transcript variants in cancer in particular fusion genes and works integrated with most of the projects mentioned above. Skotheim leads the deep sequencing platform for the CCB (see separate page).
Recent achievements The scientific production of 2010 included 17 peer review papers, one patent application, and seven academic degrees from our laboratory: Helge R. Brekke (PhD), Marianne Berg (PhD), Vera Costa (PhD), Maren Høland (M.Sc), Tone Fykerud (M.Sc), Marianne Guriby (M.Sc), Deeqa Ali (M.Sc.). PhDs. In close collaboration with the sarcoma programme at Oslo University Hospital, Radiumhospitalet and as part of a European multicentre
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study on the rare cancer disease malignant peripheral nerve sheath tumour (MPNST) Helge R Brekke published novel prognostic classifiers, including from 2010: Brekke et al., J Clin Oncol 28: 1573-1582.
The 2nd generation custom made fusion gene microarray including 600 000 oligonucleotides targeting sequences in 548 fusion genes has been run on 67 cell lines of 15 cancer types (Løvf et al., GCC 2011).
Marianne Berg defended her PhD work on young at onset colorectal cancer patients, including from 2010, Berg et al., Mol Cancer 9:100 (“highly accessed”), Berg et al., PLoSOne 5(11):e13978.
Recent/Ongoing studies. Recently, we have described novel molecular phenotype in colorectal cancer, TIN – transcriptome instability, based on exon-level transcriptomics, that is associated with poor prognosis (Sveen et al., submitted). Novel gene signature with prognostic impact of stage II and III colorectal cancers has been identified and validated in external datasets (Sveen et al., Ågesen et al., submitted). A gene expression study comparing tumors from patients younger than 50 years at disease onset with those older than 75 showed significant differences in immunity score between the groups and two of the most differentially expressed genes are IFNAR and CLC (Ågesen et al., submitted).
Vera Costa was a visiting PhD student from U of Porto. She used our methodological approach established for colorectal cancer (Lind et al., Cell Oncol 2006) to identify epigenetic markers in urological malignancies and found, among others, markers that predict bladder cancer accurately in DNA analyses of urine (Costa et al., 2010 Clin Cancer Research 16:5842-5851). Technology. We have established RNA deepsequencing protocol on the Illumina platform and are working with a protocol for exome seq. The initial data identifying novel fusion transcripts in colorectal cancer are being presented at Keystone Symposia “Changing Landscape of the Cancer Genome” in June 2011, Boston and the first manuscript is in preparation (Nome et al.).
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In collaborative projects in CCB we have identified epigenetically regulated genes that are highly suitable for early detection of colorectal cancer (Lind et al., submitted). The two commercially available DNA tests for non-invasive testing of colorectal cancer are based on single markers. We described a robust panel of markers with high
sensitivity and specificity for both carcinomas and adenomas. One of these markers, SPG20, was shown to have severe functional cellular consequence when inactivated in colorectal cancer (Lind et al., Oncogene in press; collaboration with Harald Stenmark´s group). We have in 2010 established collaboration with a Biotech company with intention to develop a non-invasive test. In additional CCB collaborative studies we have set up and compared pyrosequencing and quantitative methylation specific PCR of MGMT in brain tumors (Bentsen et al., submitted; collaboration with Sverre Heim´s group); used our methodological approach established for colorectal cancer (Lind et al., Cell Oncol 2006) to identify epigenetic markers in lymphomas (collaboration with Erlend Smeland´s group); analysed the connexin gene family for DNA promoter methylation in colorectal cancer (Sirnes et al., Epigenetics, May 2011; collaboration with Edgar Rivedal´s group). Patent application 2010 Guro E. Lind, Carmen Jeronimo, Vera Costa, Henrique Rui, Rolf I. Skotheim, Manuel R. Teixeira, Ragnhild A. Lothe. Methods and biomarkers for detection of bladder cancer. US provisional patent application filed. INVEN-31636/US-1/PRO.
Selected publications 2010 Brekke HR, Ribeiro FR, Kolberg M, Ågesen T, Eken M, Lind GE, Eknæs M, Hall KS, Bjerkehagen B, van den Berg E, Teixeira MR, Mandahl N, Smeland S, Mertens F, Skotheim RI., Lothe RA. Genomic changes in chromosome 10, 16 and X in malignant peripheral nerve sheath tumors identify a high-risk patient group. J Clin Oncol 28:1573-1582, 2010. Berg M, Ågesen TH, Thiis-Evensen E, Merok MÅ, Vatn M, Nesbakken A, Skotheim RI, Lothe RA. High resolution genome profiles of colorectal cancers from young- and old- at onset patients identify new candidate susceptibility genes. Mol Cancer, (BMC flagged as: “highly accessed”), 9:100, 2010. Berg M, Danielsen SA, Ahlquist T, Merok MA, Ågesen TH, Vatn MH, Mala T, Sjo OH, Bakka A, Moberg I, Fetveit T, Mathisen Ø, Husby A, Sandvik O, Nesbakken A, Thiis-Evensen E, Lothe RA. DNA sequence profiles of the colorectal cancer critical gene set KRAS-BRAF-PIK3CA-PTENTP53 related to age at disease onset. PLoS ONE Nov12;5(11):e13978, 2010.
Kjenseth A, Fykerud T, Rivedal E, Leithe E. Regulation of gap junction intercellular communication by the ubiquitin system. Cell Signal. 22:1267-73, 2010. Sagona AP, Nezis IP, Pedersen NM, Liestøl K, Poulton J, Rusten TE, Skotheim RI, Raiborg C, Stenmark H. PtdIns(3)P controls cytokinesis through KIF13A-mediated recruitment of FYVECENT to the midbody. Nat Cell Biol. 12:362-71, 2010. Lind, GE, Raiborg C, Danielsen SA, Rognum TO, Thiis-Evensen E, Nesbakken A, Stenmark H, Lothe RA. SPG20, a novel biomarker in colorectal carcinogenesis, encodes a regulator of cytokinesis. Oncogene, in press. Ågesen TH, Berg M, Thiis-Evensen E, Cekaite L, Merok M, Lind GE, Nesbakken A, Lothe RA, Skotheim RI. Transcriptional profiling of colorectal carcinomas from patients with 20 year age difference, identify candidate susceptibility genes. Submitted Genes Immunity.
Costa VL, Henrique R, Danielsen SA, Duarte-Pereira S, Eknaes M, Skotheim RI, Rodrigues A, Morais A, Oliveira J, Lothe RA, Teixeira MR, Jeronimo C, Lind GE. Three epigenetic biomarkers, GDF15, TMEFF2 and VIM, accurately predicts bladder cancer from DNA-based analyses of urine samples. Clinical Cancer Research, 16: 5842-5851, 2010.
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PRIZES AND AWARDS
Sir Hans Krebs Medal to Harald Stenmark
Sir Hans Krebs Medal to Harald Stenmark on the cover of The Norwegian Biochemical Society news magazine
New honorary membership for Kirsten Sandvig Kirsten Sandvig from the Department of Biochemistry at the Institute for Cancer Research has been elected as a Fellow of the American Academy of Microbiology due to her work with bacterial toxins. The Fellows are elected in recognition of their records of scientific achievement, and Sandvig is the third Norwegian to receive this honour from the academy. Fellows of the Academy are elected annually through a highly selective, peer-review process, based on their records of scientific achievement and original contributions that have advanced microbiology. There are now over 2,000 Fellows representing all subspecialties of microbiology, including basic and applied research, teaching, public health, industry, and government service.
At the 2010 FEBS Congress in Gothenburg, Harald Stenmark from the Centre for Cancer Biomedicine and the Institute for Cancer Research was awarded the Sir Hans Krebs Medal. This silver medal is awarded annually by the Federation of European Biochemical Societies for ”outstanding achievements in Biochemistry and Molecular Biology or related sciences”. The Sir Hans Krebs medal was awarded for the first time in 1968 and since then, 15 of the 38 awardees have also received the Nobel Prize. Recent awardees include Nobel laureates Aaron Ciechanover (2006) and Tim Hunt (2008). After receiving the medal, Stenmark presented a plenary lecture entitled ”How a lipid mediates tumour suppression”.
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Two articles (in Norwegian only) in NBS-Nytt 4/2010 is dedicated to this prestigious award: Stenmark tar medalje igjen and Sir Hans Krebs medalje til Harald Stenmark
FORUMS
PhD Forum After arranging a PhD Forum for PhD students in CCB in 2009, an extension of the forum to include all PhD students at the Institute for Cancer Research was initiated by the Faculty of Medicine, UiO. Two whole-day seminars were arranged during 2010, in addition to a short seminar where the core facilities of the institute were presented. The first seminar, titled “Communicating Science”, was held in June. Several experts with a diverse background were invited to share their experience on the topic, and they also gave some general advice in what to consider when communicating science to the public. Editor of the popular science news web site forskning.no, Nina Kristiansen, and science journalist Erik Tunstad, talked about how to communicate science to the media. Science journalism researcher Harald Hornmoen presented some of his observations of the interaction between science, the public and the media. Teresa Frisan gave a lecture on how to properly convey results in scientific papers, before Ole Martin Ihle, who produced the TV-series “Hjernevask”, demonstrated how dramaturgic techniques could be employed to tell scientific stories. The second seminar was called “Life after PhD – Career Opportunities” and was arranged in November. Representatives from the pharmaceutical industry, including Åge Nærdal (GlaxoSmithKline), Olav Flaten (GlaxoSmithKline) and Bjørn Klem (PhotoCure), talked about what kind of career opportunities the industry offers. Pål Kristian Selbo and Thomas Slagsvold both have background as
scientists at the Institute for Cancer Research, and they shared their stories about what influenced their own career choices. Finally, Stein Kvaløy, Head of Research at the Division of Surgery and Cancer Medicine, talked about PhD education for medical doctors. The seminars were open for everyone at the Institute, and there was a good attendance at both seminars. After each seminar there was a social event for all PhD students. For 2011 the Forum will continue to arrange semiannual events to address topics that are not lectured in courses, and also to encourage interaction between PhD students across groups, both within CCB and the Institute for Cancer Research. Jonas Bergan Member of the PhD Forum
Postdoc Forum The Postdoc Forum was established in January 2009, with the aim of providing an arena for bringing together the postdoctoral researchers within CCB, to encourage discussions and promote collaborations across the research groups. As of March 2011, approximately 40 postdoctoral researchers are associated with CCB. A committee consisting of one representative from each group within CCB is responsible for organizing the Postdoc Forum meetings. Since August 2010, all postdoctoral researchers at the Radium Hospital have been invited to attend the Postdoc Forum meetings.
In 2010, three Postdoc Forum meetings were organized. An important aim of these meetings was to share knowledge on the various state-of-the-art technologies at the Institute for Cancer Research, in order to facilitate future collaborative projects between postdoctoral researchers across scientific disciplines. Among the topics that were covered in these meetings were proteomics, flow cytometry, DNA sequencing and microarray technologies. The meetings were well-attended by postdoctoral researchers across the departments at the Radium Hospital. In 2011, we aim to continue organizing meetings on subjects that we believe are of common interest for postdoctoral researchers at the Radium Hospital. An important objective of the forum is to contribute to bridge the basic cell biology and clinically based research projects at the Radium Hospital, and researchers at the cancer clinic will be invited to give talks at the Postdoc Forum meetings. We also aim to continue organizing meetings on relevant technologies. We hope that the Postdoc Forum will be an important arena for promoting discussions and initiating interdisciplinary collaborations between postdoctoral researchers at the Radium Hospital in the years to come. Edward Leithe on behalf of the Postdoc Forum Organizing Committee
FORUMS
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COLLABORATIVE PROJECTS WITHIN CCB
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Cell division and cancer Cell division and cancer Cancer involves the ability of certain cell types to undergo uncontrolled cell divisions, and studies of the cell division process are therefore central in cancer research. CCB PhD student Antonia Sagona and her co-workers have discovered that an enzyme complex called class III phosphoinositide 3-kinase (PI3K-III) is crucial for the final stage of cell division, cytokinesis. This enzyme produces a lipid product, PtdIns3P, and Antonia and her coworkers were able to identify a PtdIns3P-binding protein, FYVE-CENT, that controls abscission between two dividing cells (Sagona et al., Nature Cell Biology, 2010). This paper was dedicated a “News and Views” commentary in Nature Cell Biology and was also highlighted on the Nature Signalling Gateway. Incorrect cytokinesis is thought to cause carcinogenesis, and Antonia and her co-workers went on to show that a mutation in FYVE-CENT that is associated with breast cancer causes cytokinesis arrest (Sagona et al., PLoS One, 2011). These findings implicate FYVE-CENT as a potential tumour suppressor, and the involvement of PI3K-III in cytokinesis might also serve to explain previous reports that this enzyme is a tumour suppressor. Hopefully, the present findings can be utilized in future work to improve cancer diagnostics and therapy. The studies of FYVECENT have involved an interdisciplinary team of cell biologists, translational cancer researchers and biostatisticians, illustrating the power of joint efforts from scientists with different expertises. The fruit fly Drosophila melanogaster offers an attractive in vivo model to study cell division and cancer, and a team led by CCB project leader Kai-
effort between cell biologists and biostatisticians in CCB. Further studies will reveal whether Cindr and its human homologue CIN85 play any role as tumour suppressors.
References Sagona AP, Nezis IP, Pedersen NM, Liestøl K, Poulton J, Rusten TE, Skotheim RI, Raiborg C and Stenmark H (2010). PtdIns3P controls cytokinesis via KIF13A-mediated recruitment of FYVECENT to the midbody. Nat.Cell Biol. 12: 361-372. Sagona AP, Nezis IP, Bache KG, Haglund K, Bakken AC, Skotheim RI and Stenmark H (2011). A tumor-associated mutation of FYVE-CENT prevents its interaction with Beclin 1 and interferes with cytokinesis. PLoS One, 30: e17086. The Phosphatidylinositol (3)-phosphate kinase Class III (green) localizes to the intercellular bridge between two dividing daughter cells. The actin cytoskeleton is shown in red and nuclei in blue. sa Haglund has recently identified a novel regulator of cytokinesis in this organism, Cindr. Cindr is a scaffold protein that interacts with other cytokinesis regulators in the intercellular bridge that separates two dividing cells, thereby controlling the cytokinesis process (Haglund et al., Current Biology, 2010). In certain tissues cytokinesis is incomplete, which results in clusters of cells that are connected by thin intercellular bridges. Cindr and one of its interacting proteins localize to these intercellular bridges, suggesting that Cindr may play a role in the regulation of complete versus incomplete cytokinesis. This project was a joint
Haglund K, Nezis IP, Lemus D, Grabbe C, Wesche J, Liestøl K, Dikic I, Palmer R and Stenmark H (2010). Cindr interacts with anillin to control cytokinesis in Drosophila melanogaster. Curr.Biol. 20: 944-950.
Cindr localizes to intercellular bridges in Drosophila cells undergoing cytokinesis. Drosophila S2 cells were fixed and stained with antibodies against Cindr (green, arrow) and α-tubulin (red), as well as with Hoechst (blue) to visualize DNA.
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Cancer biomarker CCB scientists identify a new marker for colon cancer, and reveal its cellular function The most recent example of successful interdisciplinary collaborations within CCB involves cooperation between two of the young project leaders in CCB, cancer geneticist Guro E. Lind and cell biologist Camilla Raiborg (Lind et al., Oncogene, 2011). Guro identified a very promising biomarker for early detection of colorectal cancer, the gene SPG20, which is silenced in colon cancer cells but not in normal colonic epithelium. Camilla discovered that the protein encoded by SPG20, Spartin, is a regulator of normal cell division, and that cancer cells that lack Spartin tend to be connected by intercellular membrane bridges. This is exciting since it is already known that faulty cell division can represent an early step in carcinogenesis and raises the possibility that SPG20 silencing is both a biomarker and a mechanism in colon carcinogenesis. How can these discoveries benefit the future cancer patient? Preliminary results suggest that it is possible to detect SPG20 silencing in stool samples from cancer patients, which opens the possibility of using SPG20 detection as an early diagnostic tool. Early diagnosis of colon cancer can potentially save many lives since this cancer can be successfully treated when detected early whereas it is often deadly when detected late. Moreover, knowing that cell division defects are typical for a subgroup of colorectal cancers can enable us to design therapies aimed at killing such cells – an example of personalised medicine.
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Guro E. Lind (right) and Camilla Raiborg use the confocal microscope to examine the importance of SPG20 in cell division.
Reference: Lind GE, Raiborg C, Danielsen SA, Rognum TO, Thiis-Eensen E, Hoff G, Nesbakken A, Stenmark H and Lothe RA (2011). SPG20, a novel biomarker
in colorectal carcinogenesis, encodes a regulator of cytokinesis. Oncogene, in press.
Genomics and clonality Genomics and clonality Follicular lymphoma (FL) is an indolent disease, but often transforms to a more aggressive lymphoma, usually DLBCL. We have studied a unique material consisting of serial biopsies from 44 patients with follicular lymphoma with genome-wide CGH arrays. Gains involving chromosome 2, 3q and 5 were exclusively present in FL biopsies from cases with higher grade transformation and were among the copy number alterations (CNAs) associated with inferior survival (Eide et al, Blood, 2010). Although we noted a trend for increasing genomic complexity in initial versus late FL samples, the overall frequencies of CNAs in initial and late FL biopsies revealed a surprisingly stable pattern through the course of the disease. However, in 27 patients, the initial samples harboured CNAs that were absent in relapse samples, indicating that tumour cell clones at relapse were not direct descendants of initially dominating clones. The pattern of somatic hypermutations (SHMs) confirmed parallel development of tumour cell clones in 14 cases. The findings thus support the hypothesis of common progenitor cells in FL.
Patient
Reference: Eide MB, Liestol K, Lingjaerde OC, Hystad ME, Kresse SH, Meza-Zepeda L, Myklebost O, Trøen G, Aamot HV, Holte H, Smeland EB, Delabie J (2010). Genomic alterations reveal potential for higher grade transformation in follicular lymphoma and confirm parallell evolution of tumor cell clones. Blood 116(9):1489-97.
COLLABORATIVE PROJECTS WITHIN CCB
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Autophagy and cancer Autophagy in cell death and tumour suppression Autophagy, or “self-eating”, is a process that involves degradation of portions of cytoplasm in a controlled manner. This process is thought to play two opposite roles in carcinogenesis. Under basal conditions, autophagy might suppress carcinogenesis by removing damaged organelles and abnormal cells. In contrast, when a tumour has formed, metastasizing tumour cells could exploit autophagy to generate nutritions that can be used for tumour cell survival in tissues that offer poor nutrient supply. Cancer researchers at CCB collaborate with leading national and international autophagy experts to uncover basic functions of autophagy and the importance of this process in human cancers. Autophagy can often be detected in dying cells, but it has been controversial whether autophagy is an inducer or a consequence of programmed cell death. Now, CCB postdoc Ioannis Nezis and his co-workers have used fruit flies to show an unexpected link between autophagy and programmed cell death. Ioannis and co-workers found that an inhibitor of programmed cell death, called dBruce, is degraded by autophagy at certain developmental stages, and that this triggers programmed cell death (Nezis et al., Journal of Cell Biology, 2010). Because autophagy is known to have a tumour suppressor function, these findings may be relevant to cancer as well. This study was a collabora-
34
COLLABORATIVE PROJECTS WITHIN CCB
tion with two leading laboratories in the autophagy field, the group of Terje Johansen at the University of Tromsø and the group of Eric Baehrecke at the University of Massachusetts. Translational cancer researchers at CCB have detected frequent mutations in the autophagy regulator UVRAG in a subgroup of colon cancers. Surprisingly, however, colon cancer cell lines expressing UVRAG mutations were found to have normal autophagic activity, which argues against the hypothesis that loss of autophagy is a mechanism in colon carcinogenesis (Knævelsrud et al., Autophagy, 2010). Since UVRAG is part of the PI3K-III enzyme complex, which controls cytokinesis (see elsewhere in this report), it is possible that the tumour suppressor activity of UVRAG may be related to its function in cytokinesis and not in autophagy. This study involved translational
cancer researchers, cell biologists and biostatisticians at CCB and was a collaboration with former CCB project leader Anne Simonsen, who is now leading a very successful autophagy research group at the Institute for Basic Medical Sciences.
References Nezis IP, Shravage BP, Lamark T, Rusten TE, Sagona AP, Bjørkøy G, Johansen T, Brech A, Baehrecke E and Stenmark H (2010). Autophagic degradation of inhibitor of apoptosis dBruce triggers cell death during late oogenesis in Drosophila. J. Cell Biol. 190: 523-531. Knævelsrud H, Ahlquist T, Merok MA, Nesbakken A, Stenmark H, Lothe RA and Simonsen A (2010). UVRAG mutations associated with microsatellite unstable colorectal cancer do not affect autophagy. Autophagy 6: 863-870.
Legend: dBruce (red) specifically colocalizes with the autophagic marker GFP-Atg8a (green) (arrows) in a degenerating nurse cell in a stage9 Drosopholia egg chamber (outlined).
COLLABORATIVE PROJECTS WITHIN CCB
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CCB TECHNOLOGY PLATFORMS
The deep sequencing at Centre for Cancer Biomedicine is operated by (behind from left) Ragnhild Lothe, Rolf Skotheim, Marianne Guriby, Torfinn Nome, (front from left) Gard Thomassen, and Jarle Bruun.
Deep Sequencing Technology Platform Management: Rolf I. Skotheim (leader) and Ragnhild A. Lothe At Centre for Cancer Biomedicine, we have available the Solexa technology for deep sequencing through our fifty percent ownership of an Illumina
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CCB TECHNOLOGY PLATFORMS
Genome Analyzer IIx. The sequencing is performed on flow cells with eight lanes, and each lane can produce sequences from up to 40 million DNA or RNA fragments. In addition to detection of alterations at the nucleotide-level, the technology can also be set up to detect structural changes. At CCB, we have during 2010 used this technology to perform whole-transcriptome sequencing of colorectal cancer tissues and cell lines. Of particular interest, we have now identified and experimentally validated a set of fusion genes from colorectal cancers (Nome et al., manuscript in preparation). We will integrate the RNA-seq data with data from exon microarrays and custom designed fusion gene microarrays to evaluate the importance of our findings across larger series of samples. The large amount of sequence data produced imposes challenges to data storage and processing. This is not only because of the tremendous amounts of storage and processing power required, but also due to the sensitive nature of genetic sequence data. We have at CCB established own servers on a closed network to handle data storage and processing whenever the projects involve patient data. Currently, Jarle Bruun and Marianne Guriby, Lothe group, are setting up wet lab procedure for
exome sequencing initially to be used for selected stage II colorectal cancer patients. Torfinn Nome and Gard Thomassen, Skotheim group, are setting up the informatics infrastructure and establish pipelines for bioinformatic analyses of RNA and DNA sequence data. Informatician Gard Thomassen, postdoc in Skotheim group, has been instrumental in the configuration of powerful and secure solutions for analysis of patient sensitive sequencing data at the Centre for Cancer Biomedicine.
cated at the Department of Pathology, Rikshospitalet, and the Institute of Experimental Research, Ullevål. The core facility node at Montebello was established during 2010 with funding from CCB. From 2011, it is being supported by Helse Sør-Øst in the ”Molecular Fluorescence Imaging” platform.
Confocal Microscopy Ellen Skarpen, core facility manager Harald Stenmark, core facility leader
www.rr-research.no/microscopy/
The Core facility Confocal microscopy, Montebello is located at the Department of Biochemistry. It is part of an Imaging platform at Oslo University Hospital, which includes two additional nodes lo-
During its first year, the core facility has shown a marked increase in the number of users, with a large recruitment of costumers outside CCB. The strong interest to use our services is also reflected in a high number of core facility bookings with an average of 65 reservations/month during 2010. The core facility is devoted to the application, development, and support of Advanced Fluorescence Imaging. At Montebello, we are equipped with a Zeiss LSM 710 confocal microscope with a definite focus system and incubation chamber for livecell imaging. We offer the possibility to do: Multifluorescence Imaging, Two-or three-dimensional imaging, Time Series, FRET, and FRAP, and also Image analysis and processing.
CCB TECHNOLOGY PLATFORMS
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ers at our facility in order to prepare and image samples on their own. In addition we are associated with several imaging networks, such as the NorMIC imaging platforms and the Nordic Imaging Network, which allow researchers to access high-end microscopy facilities not available in their working environment. Moreover the networking interactions are important in our efforts to stay technologically updated and to implement new techniques at the UCEM.
Cellular Electron Microscopy Andreas Brech, head of facility Marianne Smestad, technician
The Unit for Cellular Electron Microscopy (UCEM) at CCB is a state-of-the-art laboratory for ultrastructural research and image analysis. We are offering a wide range of techniques not only to researchers at CCB but also to clients from Oslo University Hospital and many national and international collaborators. We are also instructing us-
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CCB TECHNOLOGY PLATFORMS
The facility is equipped with 2 transmission elec-
tron microscopes (a Philips CM10 and JEOL-JEM 1230) and provides researchers with a wide variety of specimen preparation methods. We perform conventional plastic embedding of samples as well as specialized methods for cryopreservation and cryosectioning. Immunogold techniques for molecular distribution studies are well established along with image analysis with quantification of structure and marker density in the different tissue components of interest. We also perform correlative light and electron microscopy (CLEM), a technique that combines image information from and bridges the resolution gap between light and electron microscopy. We are currently implementing techniques for cryopreservation and freeze substitution/low temperature embedding, which enhance structural preservation. This is important in conjunction with the installation of tomography software for 3-dimensional reconstruction of subcellular structures.
DEGREES
PhD degrees 2010
Master degrees 2010
Yan Zhen PhD – Intracellular trafficking and signaling of fibroblast growth factor 1 and its receptor Faculty of Medicine, University of Oslo, April 2010
Marianne Guriby, M.Sc. in Molecular Biology – New epigenetic biomarkers examined for added value in lymph node diagnostics of colon cancer University of Life Sciences at Ås, February 2010
Wanja Kildal PhD – DNA ploidy as a prognostic marker in selected gynecological malignancies Faculty of Medicine, University of Oslo, June 2010 Helge Roar Brekke PhD – New insights into the biology of Malignant Peripheral nerve Sheath Tumors identify biomarkers for disease outcome Faculty of Medicine, University of Oslo, June 2010 Marianne Berg PhD – Genomics of colorectal carcinomas from young and elderly patients Faculty of Medicine, University of Oslo, October 2010
Deeqa Ali, M.Sc. in Molecular Biosciences – Identification of novel epigenetic biomarkers in colorectal cancer, GLDC and PPP1R14A Faculty of Mathematics and Natural Sciences, University of Oslo, March 2010 Ieva Ailte, M.Sc. in Molecular Biosciences – The role of SNX8 in Retrograde Transport of Shiga Toxin2 Faculty of Mathematics and Natural Sciences, University of Oslo, June 2010
Tone Aase Fykerud, M.Sc. in Molecular Biosciences – Regulation of the gap junction protein connexin43 by members of the Nedd4 E3 ubiquitin ligase family Faculty of Mathematics and Natural Sciences, University of Oslo, June 2010 Maren Høland, M.Sc. in Molecular Biosciences – Prognostic value of protein markers in malignant peripheral nerve sheath tumours Faculty of Mathematics and Natural Sciences, University of Oslo, August 2010 Santosh Phuyal, M.Sc. in Molecular Biology – The role of lipids in the release of exosomes from the human prostate cancer PC-3 cell line University of Life Sciences at Ås, December 2010
DEGREES
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CCB SEMINARS
CCB Seminars 2010 Role of heparan sulfate in fibroblast growth factor (FGF) signaling: a lesson from FGF1 engineering Speaker: Antoni Wiedlocha, PhD - CCB, Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital Date: 19 January 2010
Public lecture by CCB scientists Three lectures on cancer was given by CCB scientists in an event open to the public, organised by The Natural History Museum at the University of Oslo.
“Tykktarmskreft – en vanlig og alvorlig diagnose. Forskning gir håp om bedret livskvalitet og overlevelse” Speaker: Prof. Ragnhild A. Lothe – CCB, Department of Cancer Prevention, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital “Ny og presis tidligdiagnostikk av tykktarmskreft” Speaker: Dr. Guro Elisabeth Lind – CCB, Department of Cancer Prevention, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital Date: 8 May 2010
The annual CCB seminar 2010 The third annual seminar in CCB history was arranged at Hotel Leangkollen in Asker. More than hundred CCB members participated in this two day event where scientific presentations and discussions as well as social gathering were the focus of attention. This annual get-together is a great boost for the common CCB spirit. Date: 26-27 August 2010
Radiosensitizing properties of vorinostat in preclinical studies and clinical radiotherapy Speaker: Kjersti Flatmark, MD, PhD – Department of Tumor Biology and Surgical Oncology, The Norwegian Radium Hospital, Oslo University Hospital
Programme (in Norwegian): “Hva er kreft, og hvordan kan grunnforskning bidra til å hjelpe fremtidens kreftpasienter?” Speaker: Prof. Harald Stenmark - CCB, Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital
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CCB SEMINARS
SPG20 is a biomarker for colorectal cancer and has a function in cytokinesis Speaker: Camilla Raiborg, PhD – CCB, Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, and Speaker: Guro E. Lind, PhD – CCB, Department of Cancer Prevention, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital Date: 21 June 2010
An exploration of transcriptional control in prostate cancer implicates calcium/calmodulin regulated kinases as biomarkers and therapeutic targets Speaker: Dr Ian Mills – The Prostate Cancer Research Group, Nordic EMBL Partnership, Centre for Molecular Medicine Norway (NCMM), University of Oslo Date: 28 September 2010
Sphingosine 1-phosphate in cancer : a new therapeutic target Guest lecture by Olivier Cuvillier, PhD, Researcher in Biochemistry and Head of the Sphingolipids and Cancer Research Laboratory in Toulouse. Date: 29 September 2010
Targeting cancer with high affinity T cells Speaker: Johanna Olweus, Professor, MD, PhD – Department of Immunology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital Autophagy and cell death Speaker: Ioannis Nezis, PhD – CCB, Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital Date: 23 November 2010
Seminar about cell division by Professor Daniel Gerlich Guest lecture by Daniel Gerlich from the ETH in Zürich, one of the leading scientists on studies of cell division and its relation to cancer: “Bridging
spatial and temporal resolution gaps in the study of cell division”. The seminar was sponsored by Norsk Hydro’s Fund for Cancer Research. Date: 17 December 2010
Poster Seminar – Presentation of ongoing CCB projects During this event CCB gave a broad presentation of its ongoing research projects by showing 66 posters grouped in 4 categories: Biomarkers in cancer, Cell signaling in cancer, Genomics, epigenomics and proteomics, and Bioinformatics and imaging tools for cancer research. CCB had the pleasure to invite colleagues from the Institute for Cancer Research and from the Division of Surgery and Cancer Medicine at the Norwegian Radium Hospital to join in for scientific discussions followed by social gathering, tapas and wine. Date: 27 January 2011
All CCB seminars are open to the Institute for Cancer Research and the Division of Surgery & Cancer Medicine
Three CCB groups appointed as “Helse Sør-Øst Forskningsgruppe”
According to announcements from the SouthEastern Norway Regional Health Authority (Helse Sør-Øst) in December 2010, as many as three groups from CCB have been awarded in the top category, “Helse Sør-Øst forskningsgruppe”. The three groups are those of Harald Stenmark, Ragnhild A. Lothe and Kirsten Sandvig. During the period 2011-2013 each group will receive NOK 3 mill. annually from Helse Sør-Øst.
Kirsten Sandvig
Ragnhild A. Lothe
Harald Stenmark
CCB SEMINARS
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VISITORS TO AND FROM CCB
Visitors to CCB in 2010
Courses
Hosted at Antoni Wiedlocha’s lab: • Anna Szlachcic, PhD student from the University of Wroclaw, Poland From September to October 2010 (1 month) • Anna Pryszak, Master student from the University of Gdansk, Poland. From July to August 2010 (1,5 months)
MBV3020 “Molecular Genetics and Developmental Biology” Faculty of Mathematics and Natural Sciences, University of Oslo, November 2010 Responsible for “Cancer Biology session”: Ragnhild A. Lothe Lecturers from CCB: Ragnhild A. Lothe, Guro Lind, Edgar Rivedal, Edward Leithe, Gard Thommassen.
Hosted at Ragnhild A. Lothe’s lab: • Ricardo Celestino, PhD student from the University of Porto, Portugal From June to July 2010 (2 months) • Paula Paulo, PhD student from the Portuguese Oncology Institute, Portugal From July to August 2010 (2 months)
Guest visits abroad in 2010: Hosted at Jim Norman’s lab at Beatson Institute for Cancer Research, Scotland: • Ellen M. Haugsten, Postdoc from Antoni Wiedlocha’s lab From July to December 2010 (6 months) Hosted at Ron Levy’s lab at Stanford University, USA: • June H. Myklebust, Project leader from Erlend Smeland’s lab March 2010 (1 month)
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EDUCATIONAL ACTIVITIES
VISITORS TO AND FROM CCB
MBV4240/9240 “Biochemical Mechanisms in Intracellular Transport” Faculty of Mathematics and Natural Sciences, University of Oslo, Autumn 2010 Course responsible: Kirsten Sandvig Lecturers from CCB: Kirsten Sandvig, Antoni Wiedlocha, Harald Stenmark. MBV9100 BTS “Molecular Biology Research Course” Biotechnology Centre of Oslo, University of Oslo, Autumn 2010 Lecturer from CCB: June H. Myklebust, Rolf I. Skotheim.
MBV9270 “BIOSTRUCT - Advanced Glycobiology” Faculty of Mathematics and Natural Sciences, University of Oslo, Spring 2010 Lecturer from CCB: Kirsten Sandvig. MF9170 “Flow Cytometry in Medical Research and Diagnostics” Faculty of Medicine, University of Oslo, Autumn 2010 Lecturer from CCB: June H. Myklebust. MOL8006 “Receptor Signalling and Trafficking” Faculty of Medicine at the University of Trondheim, Spring 2010 Course responsible: Harald Stenmark Lecturers from CCB: Harald Stenmark, Tor Erik Rusten, Hilde Abrahamsen, Jørgen Wesche, Lene Malerød.
MBV9200 BTS “Molecular Medicine in Cancer and Immunology” Biotechnology Centre of Oslo, University of Oslo, Autumn 2010 Lecturers from CCB: June H. Myklebust, Antoni Wiedlocha, Rolf I. Skotheim.
EDUCATIONAL ACTIVITIES
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PUBLICATIONS AND PRESENTATIONS
Publications 2010 Abrahamsen H, Stenmark H. (2010) Protein secretion: unconventional exit by exophagy Curr Biol. 20(9):R415-8. Bakkebø M, Huse K, Hilden VI, Smeland EB, Oksvold MP. (2010) TGF-β-induced growth inhibition in B-cell lymphoma correlates with Smad1/5 signalling and constitutively active p38 MAPK BMC Immunol. 2010 11:57. Berg M, Agesen TH, Thiis-Evensen E, Infac IS, Merok MA, Teixeira MR, Vatn MH, Nesbakken A, Skotheim RI, Lothe RA. (2010) Distinct high resolution genome profiles of early onset and late onset colorectal cancer integrated with gene expression data identify candidate susceptibility loci Mol Cancer. 9(1):100. Berg M, Danielsen SA, Ahlquist T, Merok MA, Ågesen TH, Vatn MH, Mala T, Sjo OH, Bakka A, Moberg I, Fetveit T, Mathisen Ø, Husby A, Sandvik O, Nesbakken A, Thiis-Evensen E, Lothe RA. (2010) DNA sequence profiles of the colorectal cancer critical gene set KRAS-BRAF-PIK3CAPTEN-TP53 related to age at disease onset PLoS ONE 5(11):e13978. Borgan E, Sitter B, Lingjærde OC, Johnsen H, Lundgren S, Bathen TF, Sørlie T, BørresenDale AL, Gribbestad IS. (2010) Merging transcriptomics and metabolomics - advances in breast cancer profiling BMC Cancer 10:628.
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PUBLICATIONS AND PRESENTATIONS
Brandal P, Teixeira MR, Heim S. (2010) Genotypic and phenotypic classification of cancer: How should the impact of the two diagnostic approaches best be balanced? Genes Chromosomes Cancer. 49(9):763-74. Brekke HR, Ribeiro FR, Kolberg M, Agesen TH, Lind GE, Eknæs M, Hall KS, Bjerkehagen B, van den Berg E, Teixeira MR, Mandahl N, Smeland S, Mertens F, Skotheim RI, Lothe RA. (2010) Genomic Changes in Chromosomes 10, 16, and X in Malignant Peripheral Nerve Sheath Tumors Identify a High-Risk Patient Group J Clin Oncol. 28(9):1573-82. Burum-Auensen E, Skotheim RI, Schjølberg AR, Røislien J, Lothe RA, Clausen OP. (2010) Spindle proteins are differentially expressed in the various histological subtypes of testicular germ cell tumors J Carcinog. 9:1. Chao MP, Alizadeh AA, Tang C, Myklebust JH, Varghese B, Gill S, Jan M, Cha AC, Chan CK, Tan BT, Park CY, Zhao F, Kohrt HE, Malumbres R, Briones J, Gascoyne RD, Lossos IS, Levy R, Weissman IL, Majeti R. (2010) Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma Cell. 142(5):699-713. Clausen TH, Lamark T, Isakson P, Finley K, Larsen KB, Brech A, Overvatn A, Stenmark H, Bjørkøy G, Simonsen A, Johansen T. (2010) p62/SQSTM1
and ALFY interact to facilitate the formation of p62 bodies/ALIS and their degradation by autophagy Autophagy. 6(3):330-44. Costa VL, Henrique R, Danielsen SA, DuartePereira S, Eknaes M, Skotheim RI, Rodrigues A, Magalhães JS, Oliveira J, Lothe RA, Teixeira MR, Jeronimo C, Lind GE. (2010) Three epigenetic biomarkers, GDF15, TMEFF2 and VIM, accurately predict bladder cancer from DNAbased analyses of urine samples Clin Cancer Res. 16(23):5842-51. Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB, Kohlhammer H, Lamy L, Zhao H, Yang Y, Xu W, Shaffer AL, Wright G, Xiao W, Powell J, Jiang JK, Thomas CJ, Rosenwald A, Ott G, Muller-Hermelink HK, Gascoyne RD, Connors JM, Johnson NA, Rimsza LM, Campo E, Jaffe ES, Wilson WH, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Pierce SK, Staudt LM. (2010) Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma Nature 463:8892. Eide MB, Liestol K, Lingjaerde OC, Hystad ME, Kresse SH, Meza-Zepeda L, Myklebost O, Trøen G, Aamot HV, Holte H, Smeland EB, Delabie J. (2010) Genomic alterations reveal potential for higher grade transformation in follicular lymphoma and confirm parallel evolution of tumor cell clones Blood. 116(9):1489-97.
Falster DS, Nakken S, Bergem-Ohr M, Rødland EA, Breivik J. (2010) Unstable DNA repair genes shaped by their own sequence modifying phenotypes J Mol Evol. 70(3):266-74. Filimonenko M, Isakson P, Finley KD, Anderson M, Jeong H, Melia TJ, Bartlett BJ, Myers KM, Birkeland HC, Lamark T, Krainc D, Brech A, Stenmark H, Simonsen A, Yamamoto A. (2010) The selective macroautophagic degradation of aggregated proteins requires the PI3P-binding protein Alfy Mol Cell. 38(2):265-79. Groves B, Abrahamsen H, Clingan H, Frantz M, Mavor L, Bailey J, Ma D. (2010) An inhibitory role of the G-protein regulator AGS3 in mTOR-dependent macroautophagy PLoS One 5:e8877. Haglund K, Nezis IP, Lemus D, Grabbe C, Wesche J, Liestøl K, Dikic I, Palmer R and Stenmark H. (2010) Cindr interacts with anillin to control cytokinesis in Drosophila melanogaster Curr Biol. 20(10):944-50. Haugsten EM, Wiedlocha A, Olsnes S, Wesche J. (2010) Roles of fibroblast growth factor receptors in carcinogenesis Mol Cancer Res. 8(11):1439-52. Haakensen VD, Biong M, Lingjærde OC, Holmen MM, Frantzen JO, Chen Y, Navjord D,
Romundstad L, Lüders T, Bukholm IK, Solvang HK, Kristensen VN, Ursin G, Børresen-Dale AL, Helland A. (2010) Expression levels of uridine 5’-diphospho-glucuronosyltransferase genes in breast tissue from healthy women are associated with mammographic density Breast Cancer Res. 12(4):R65. Iglesias R, Citores L, Ferreras JM, Pérez Y, Jiménez P, Gayoso MJ, Olsnes S, Tamburino R, Di Maro A, Parente A, Girbés T. (2010) Sialic acidbinding dwarf elder four-chain lectin displays nucleic acid N-glycosidase activity Biochimie 92:71-80. Irish JM, Myklebust JH, Alizadeh AA, Houot R, Sharman JP, Czerwinski DK, Nolan GP, Levy R. (2010) B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progression Proc Natl Acad Sci USA. 107(29):12747-54. Iversen TG, Frerker N, Sandvig K. (2010) Endocytosis and intracellular trafficking of quantum dot-ligand bioconjugates in OrganelleSpecific Pharmaceutical Nanotechnology (Weissig V, D’Souza GG. eds., ISBN 978-0-470-63165-2)), pp. 55-72, Wiley & Sons, New Jersey, USA. Kjenseth A, Fykerud T, Rivedal E, Leithe E. (2010) Regulation of gap junction intercellular communication by the ubiquitin system Cell Signal. 22(9):1267-73.
Knævelsrud H, Ahlquist T, Merok MA, Nesbakken A, Stenmark H, Lothe RA, Simonsen A. (2010) UVRAG mutations associated with microsatellite unstable colon cancer do not affect autophagy Autophagy. 6(7):863-70. Leithe E, Kjenseth A, Bruun J, Sirnes S, Rivedal E. (2010) Inhibition of Connexin43 gap junction channels by the endocrine disruptor ioxynil Toxicol Appl Pharmacol. 247(1):10-7. Lobert VH, Brech A, Pedersen NM, Wesche J, Oppelt A, Malerød L, Stenmark H. (2010) Ubiquitination of alpha 5 beta 1 integrin controls fibroblast migration through lysosomal degradation of fibronectin-integrin complexes Dev Cell. 19(1):148-59. Luo RF, Zhao S, Tibshirani R, Myklebust JH, Sanyal M, Fernandez R, Gratzinger D, Marinelli RJ, Lu ZS, Wong A, Levy R, Levy S, Natkunam Y. (2010) CD81 protein is expressed at high levels in normal germinal center B cells and in subtypes of human lymphomas Hum Pathol. 41(2):271-80. Micci F, Haugom L, Ahlquist T, Abeler VM, Trope CG, Lothe RA, Heim S. (2010) Tumor spreading to the contralateral ovary in bilateral ovarian carcinoma is a late event in clonal evolution J Oncol. 2010:646340.
PUBLICATIONS AND PRESENTATIONS
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Micci F, Haugom L, Ahlquist T, Andersen HK, Abeler VM, Davidson B, Trope CG, Lothe RA, Heim S. (2010) Genomic aberrations in borderline ovarian tumors J Transl Med. 8:21. Micci F, Skotheim RI, Haugom L, Weimer J, Eibak AM, Abeler VM, Trope CG, Arnold N, Lothe RA, Heim S. (2010) Array-CGH analysis of microdissected chromosome 19 markers in ovarian carcinoma identifies candidate target genes Genes Chromosomes Cancer. 49(11):1046-53. Nakken S, Rødland EA, Hovig E. (2010) Impact of DNA physical properties on local sequence bias of human mutation Hum Mutat. 31(12):1316-25. Nezis IP, Sagona AP, Schink KO, Stenmark H. (2010) Divide and ProsPer: The emerging role of PtdIns3P in cytokinesis Trends Cell Biol. 20(11):642-9. Nezis IP, Shravage BV, Sagona AP, Johansen T, Baehrecke EH, Stenmark H. (2010) Autophagy as a trigger for cell death: Autophagic degradation of inhibitor of apoptosis dBruce controls DNA fragmentation during late oogenesis in Drosophila Autophagy. 6(8). Nezis IP, Shravage BV, Sagona AP, Lamark T, Bjørkøy G, Johansen T, Rusten TE, Brech A, Baehrecke EH, Stenmark H. (2010) Autophagic degradation of dBruce controls DNA fragmentation in nurse cells during late
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PUBLICATIONS AND PRESENTATIONS
Drosophila melanogaster oogenesis J Cell Biol. 190(4):523-31. Pankiv S, Alemu EA, Brech A, Bruun JA, Lamark T, Overvatn A, Bjørkøy G, Johansen T. (2010) FYCO1 is a Rab7 effector that binds to LC3 and PI3P to mediate microtubule plus end-directed vesicle transport J Cell Biol. 188:253-69. Pinheiro M, Ahlquist T, Danielsen SA, Lind GE, Veiga I, Pinto C, Costa VL, Afonso L, Sousa O, Fragoso M, Santos L, Henrique R, Lopes P, Lopes C, Lothe RA, Teixeira MR. (2010) Colorectal carcinomas with microsatellite instability display a different pattern of target gene mutations according to large bowel site of origin BMC Cancer. 10(1):587. Potapenko IO, Haakensen VD, Lüders T, Helland A, Bukholm I, Sørlie T, Kristensen VN, Lingjaerde OC, Børresen-Dale AL. (2010) Glycan gene expression signatures in normal and malignant breast tissue; possible role in diagnosis and progression Mol Oncol. 4(2):98-118. Pradhan M, Abeler VM, Davidson B, Kildal W, Nybøen A, Tropé CG, Risberg B, Danielsen HE. (2010) DNA ploidy heterogeneity in endometrial carcinoma: comparison between curettage and hysterectomy specimens Int J Gynecol Pathol. 29(6):572-8. Pust S, Barth H, Sandvig K. (2010) Clostridium botulinum C2 toxin is internalized by clathrinand Rho-dependent mechanisms Cell Microbiol. 12(12):1809-20.
Pust S, Dyve AB, Torgersen ML, van Deurs B, Sandvig K. (2010) Interplay between toxic transport and flotillin localization PLoS ONE 5:e8844. Rivedal E, Witz G, Leithe E. (2010) Gap junction intercellular communication and benzene toxicity Chem Biol Interact. 184(1-2):229-32. Roxrud I, Stenmark H, Malerød L. (2010) ESCRT & Co. Biol Cell. 102(5):293-318. Rui L, Emre NC, Kruhlak MJ, Chung HJ, Steidl C, Slack G, Wright GW, Lenz G, Ngo VN, Shaffer AL, Xu W, Zhao H, Yang Y, Lamy L, Davis RE, Xiao W, Powell J, Maloney D, Thomas CJ, Möller P, Rosenwald A, Ott G, Muller-Hermelink HK, Savage K, Connors JM, Rimsza LM, Campo E, Jaffe ES, Delabie J, Smeland EB, Weisenburger DD, Chan WC, Gascoyne RD, Levens D, Staudt LM. (2010) Cooperative epigenetic modulation by cancer amplicon genes Cancer Cell. 18(6):590-605. Russnes HG, Vollan HK, Lingjaerde OC, Krasnitz A, Lundin P, Naume B, Sørlie T, Borgen E, Rye IH, Langerød A, Chin SF, Teschendorff AE, Stephens PJ, Månér S, Schlichting E, Baumbusch LO, Kåresen R, Stratton MP, Wigler M, Caldas C, Zetterberg A, Hicks J, Børresen-Dale AL. (2010) Genomic architecture characterizes tumor progression paths and fate in breast cancer patients Sci Transl Med. 2(38):38ra47. Rusten TE, Stenmark H. (2010) p62, an autophagy hero or culprit? Nat Cell Biol. 12:207.
Sagona AP, Nezis IP, Pedersen NM, Liestøl K, Poulton J, Rusten TE, Skotheim RI, Raiborg C, Stenmark H. (2010) PtdIns3P controls cytokinesis via KIF13A-mediated recruitment of FYVE-CENT to the midbody Nat Cell Biol. 12(4):362-71. Sagona AP, Stenmark H. (2010) Cytokinesis and cancer FEBS Lett. 584(12):2652-61. Sandvig K, Bergan J, Dyve AB, Skotland T, Torgersen ML. (2010) Endocytosis and retrograde transport of Shiga toxin Toxicon. 56(7):1181-5. Sandvig K, Torgersen ML, Engedal N, Skotland T, Iversen TG. (2010) Protein toxins from plants and bacteria: Probes for intracellular transport and tools in medicine FEBS Lett. 584(12):262634. Santos J, Cerveira N, Bizarro S, Ribeiro FR, Correia C, Torres L, Lisboa S, Vieira J, Mariz JM, Norton L, Snijder S, Mellink CH, Buijs A, Shih LY, Strehl S, Micci F, Heim S, Teixeira MR. (2010) Expression pattern of the septin gene family in acute myeloid leukemias with and without MLL-SEPT fusion genes Leuk Res. 34(5):61521. Sem-Wegner C, Malerød L, Pedersen NM, Bakke O, Stenmark H, Brech A. (2010) Ultrastructural characterization of giant endosomes induced by GTPase-deficient Rab5 Histochem. Cell Biol. 33:41-55 (Selected for cover image).
Shimokawa N, Haglund K, Hölter SM, Grabbe C, Kirkin V, Koibuchi N, Schultz C, Rozman J, Hoeller D, Qiu CH, Londoño MB, Ikezawa J, Jedlicka P, Stein B, Schwarzacher SW, Wolfer DP, Ehrhardt N, Heuchel R, Nezis I, Brech A, Schmidt MH, Fuchs H, Gailus-Durner V, Klingenspor M, Bogler O, Wurst W, Deller T, de Angelis MH, Dikic I. (2010) CIN85 regulates dopamine receptor endocytosis and governs behaviour in mice EMBO J. 29(14):2421-32. Skotland T, Iversen TG, Sandvig K. (2010) New metal-based nanoparticles for intravenous use: requirements for clinical success with focus on medical imaging Nanomedicine 6(6):730-7. Stuffers S, Malerød L, Schink KO, Corvera S, Stenmark H, Brech A. (2010) Timeresolved Ultrastructural Detection of Phosphatidylinositol 3-phosphate J Histochem Cytochem. 58(11):1025-32. Sørlie T, Borgan E, Myhre S, Vollan HK, Russnes H, Zhao X, Nilsen G, Lingjaerde OC, BørresenDale AL, Rødland E. (2010) The importance of gene-centring microarray data Lancet Oncol. 11(8):719-20; author reply 720-1. Tekpli X, Rivedal E, Gorria M, Landvik NE, Rissel M, Dimanche-Boitrel MT, Baffet G, Holme JA, Lagadic-Gossmann D. (2010) The B[a] P-increased intercellular communication via translocation of connexin-43 into gap junctions
reduces apoptosis Toxicol Appl Pharmacol. 242:231-40. Thoresen SB, Pedersen NM, Liestøl K, Stenmark H. (2010) A phosphatidylinositol 3-kinase class III sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates cytokinesis and degradative endocytic traffic Exp Cell Res. 316(20):3368-78. Tjeldhorn L, Iversen N, Sandvig K, Bergan J, Sandset PM, Skretting G. (2010) Functional characterization of the protein C A267T mutation: evidence for impaired secretion due to defective intracellular transport BMC Cell Biol. 11(1):67. Torgersen ML, Engedal N, Bergan J, Sandvig K. (2010) The intracellular journey of Shiga toxins The Open Toxinology Journal, Bentham Science 3:3-12. Utskarpen A, Massol R, van Deurs B, Lauvrak SU, Kirchhausen T, Sandvig K. (2010) Shiga toxin increases formation of clathrin-coated pits through Syk kinase PLoS One. 5(7):e10944. Van Loo P, Nordgard SH, Lingjærde OC, Russnes HG, Rye IH, Sun W, Weigman VJ, Marynen P, Zetterberg A, Naume B, Perou CM, BørresenDale AL, Kristensen VN. (2010) Allele-specific copy number analysis of tumors Proc Natl Acad Sci U S A. 107(39):16910-5.
PUBLICATIONS AND PRESENTATIONS
47
Wang L, Jin Y, Arnoldussen YJ, Jonson I, Qu S, Mælandsmo GM, Kristian A, Risberg B, Wæhre H, Danielsen HE, Saatcioglu F. (2010) STAMP1 Is Both a Proliferative and an Antiapoptotic Factor in Prostate Cancer Cancer Res. 70(14):5818-28. Zwierzina H, Bardelli A, Ciardiello F, Gariboldi M, Håkansson L, Lambrechts D, Lind GE, Loeffler-Ragg J, Schmoll H, Siena S, Tabernero J, Van Cutsem E. (2010) Molecularly Targeted Therapies for Colorectal Cancer: Strategies for Implementing Translational Research in Clinical Trials Current Opinion in Molecular Therapeutics 12(6):703-11.
Publications 2011 Bartlett BJ, Isakson P, Lewerenz J, Sanchez H, Kotzebue RW, Cumming RC, Harris GL, Nezis IP, Schubert DR, Simonsen A, Finley KD. (2011) p62, Ref(2)P and ubiquitinated proteins are conserved markers of neuronal aging, aggregate formation and progressive autophagic defects Autophagy. Jun 1;7(6). Engedal N, Skotland T, Torgersen ML, Sandvig K. (2011) Shiga toxin and its use in targeted cancer therapy and imaging Microb Biotechnol. 4(1):32-46. Løvf M, Thomassen GO, Bakken AC, Celestino R, Fioretos T, Lind GE, Lothe RA, Skotheim RI. (2011) Fusion gene microarray reveals cancer type-specificity among fusion genes Genes Chromosomes Cancer. May 50(5):348-57.
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PUBLICATIONS AND PRESENTATIONS
Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH, Kohlhammer H, Xu W, Yang Y, Zhao H, Shaffer AL, Romesser P, Wright G, Powell J, Rosenwald A, Muller-Hermelink HK, Ott G, Gascoyne RD, Connors JM, Rimsza LM, Campo E, Jaffe ES, Delabie J, Smeland EB, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Staudt LM. (2011) Oncogenically active MYD88 mutations in human lymphoma Nature. 470(7332):115-9.
Dahlback HS, Gorunova L, Brandal P, Scheie D, Helseth E, Meling TR, Heim S. (2011) Genomic aberrations in diffuse low-grade gliomas Genes Chromosomes Cancer. 2011 Mar 15 [Epub ahead of print].
Sirnes S, Honne H, Ahmed D, Danielsen SA, Rognum TO, Meling GI, Leithe E, Rivedal E, Lothe RA, Lind GE. (2011) DNA methylation analyses of the connexin gene family reveal silencing of GJC1 (Connexin45) by promoter hypermethylation in colorectal cancer Epigenetics. May 1;6(5).
Sandve GK, Gundersen S, Rydbeck H, Glad IK, Holden L, Holden M, Liestøl K, Clancy T, Ferkingstad E, Johansen M, Nygaard V, Tøstesen E, Frigessi A, Hovig E. (2010) The Genomic HyperBrowser: inferential genomics at the sequence level Genome Biol. 2010 Dec 23;11(12):R121 [Epub ahead of print].
Torgersen ML, Engedal N, Pedersen AM, Husebye H, Espevik T, Sandvig K. ( 2011) Toll-like receptor 4 facilitates binding of Shiga toxin to colon carcinoma and umbilical vein endothelial cells FEMS Immunol. Med. Microbiol. 61(1):63-75.
Sandvig K, Pust S, Skotland T, van Deurs B. (2011) Clathrin-independent endocytosis: Mechanisms and function Curr. Opin. Cell Biol. (In Press).
Publications in press Berge G, Costea DE, Berg M, Rasmussen H, Grotterød I, Lothe RA, Mælandsmo GM, Flatmark K. (2010) Coexpression and nuclear colocalization of metastasis-promoting protein S100A4 and p53 without mutual regulation in colorectal carcinoma Amino Acids 2010 Feb 27 [Epub ahead of print].
Iversen TG, Skotland T, Sandvig K. (2011) Endocytosis and intracellular transport of nanoparticles: Present knowledge and need for future studies Nano Today (In Press).
Sokołowska I, Wälchli S, Wegrzyn G, Sandvig K, Słomińska-Wojewódzka M. (2011) A single point mutation in ricin A-chain increases toxin degradation and inhibits EDEM1-dependent ER retrotranslocation Biochem J. 2011 Mar 9 [Epub ahead of print]. Zakrzewska M, Sørensen V, Jin Y, Wiedlocha A, Olsnes S. (2011) Translocation of exogenous FGF1 into cytosol and nucleus is a periodic event independent of receptor kinase activity Exp Cell Res. 2011 Jan 8. [Epub ahead of print].
Invited Lectures/Selected Presentations Iversen T-G.: ”Cellular delivery and intracellular trafficking of nanoparticles” at the 3rd International Symposium “Cellular Delivery of Therapeutic Macromolecules 2010”, June 26-29, 2010, Cardiff University, Wales, UK. Myklebust J.: “NF-kB Signaling In Response to CpG Stratifies Mantle Cell Lymphoma Patient Outcome”. Conference: American Society of Hematology, December 4-7, 2010, Orlando, USA. Myklebust J.: “Multiparameter FACS analysis of intracellular signaling pathways in human cells”. Invited lecturer at Nordic BD FACS user meeting, November 9-10, 2010, Helsinki, Finland. Myklebust J.: ”Phospho-protein specific flow cytometry identifies signaling profiles in cancer cells and infiltrating T cells with prognostic power in B cell lymphoma”. Invited lecturer at Centrum för Infektionsmedicin (CIM), Karolinska Universitetssjukhuset, November 17, 2010, Huddinge, Sweden. Rivedal E.: ”Mechanisms involved in benzeneinduced leukemia and hematotoxicity”. 15th International Charles Heidelberger Symposium on Cancer Research, 2010, Phitsanulok, Thailand. Sandvig K.: ”Protein toxins from plants and bacteria: probes for intracellular transport and tools in medicine”. Plenary lecture at FEBS-meeting, June 26-July 1, 2010, Gothenburg, Sweden.
Sandvig K.: ”Endocytosis and retrograde transport of Shiga toxin”. The 2010 Gordon Research Conference on “Microbial Toxins and Pathogenicity”, July 11-16, 2010, NH, USA.
Stenmark H.: “How a lipid mediates tumour suppression”. Invited keynote speaker at the International Symposium on Organelle Network, July 12-13, 2010, Osaka, Japan.
Sandvig K.: ”Endocytosis and retrograde transport of Shiga toxin”. EMBO meeting ”At the joint edge of cellular microbiology & cell biology”, October 9-14, 2010, Krakow, Poland.
Stenmark H.: “Class III PI 3-kinase in membrane dynamics and tumour suppression”. Guest lecturer at the IFOM Institute, October 17, 2010, Milan, Italy.
Skotheim RI.: ”RNA transcript variants specific to malignant pluripotent cells: Keys to development of TGCT”. Invited speaker at the 7th Copenhagen Workshop CIS testis and germ cell cancer, October 13-15, 2010, Copenhagen, Denmark.
Wesche J.: ”Endosomal escape: lessons learnt from FGF1” at the 3rd International Symposium “Cellular Delivery of Therapeutic Macromolecules 2010”, June 26-29, 2010, Cardiff University, UK.
Stenmark H.: Krebs Medal Review: “How a lipid mediates tumour suppression”. Keynote lecture at the 35th annual congress of the Federation of European Biochemical Societies, June 26-July 1, 2010, Gothenburg, Sweden. Stenmark H.: “Degradative integrin trafficking and its role in cell migration”. Invited speaker at the “Vesicular Transport and Cancer” meeting, June 7-9, 2010, Turku, Finland.
Wiedlocha A.: ”Activation and termination of fibroblast growth factor (FGF) induced cellular signaling”. Guest lecturer at International Institute of Molecular and Cell Biology, October 28, 2010, Warszawa, Poland. Wiedlocha A.: ”Fibroblast growth factor induced signaling and development of malignant phenotype”. Guest lecturer at Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, April 28, 2010, Wroclaw, Poland.
Stenmark H.: “Endosomal sorting in control of cell signalling and migration”. Invited speaker at the Gordon Research Conference on Lysosomes and Endocytosis, June 20-24, 2010, Andover, New Hampshire, USA.
PUBLICATIONS AND PRESENTATIONS
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COLLABORATIONS
National collaboration 2010 Ph.D. student Lena Tjeldhorn, Department of Hematology, Oslo University Hospital, Ullevål
Prof. Fritz Albregtsen, Faculty of Mathematics and Natural Sciences, Department of Informatics, University of Oslo
Arne Kolstad, MD, PhD, Division of Surgery and Cancer Medicine, Oslo University Hospital, The Norwegian Radium Hospital
Prof. Oddmund Bakke, Faculty of Mathematics and Natural Sciences, Department of Molecular Biosciences, University of Oslo
Prof. Ute Krengel, Faculty of Mathematics and Natural Sciences, Department of Chemistry, University of Oslo
Egil Blix, Department of Oncology, University Hospital North Norway, Tromsø and Department of Immunology, University of Tromsø
Prof. Stein Kvaløy, Division of Surgery and Cancer Medicine, Oslo University Hospital, The Norwegian Radium Hospital
Michael Bretthauer MD, PhD, The Cancer Registry of Norway, Oslo University Hospital
Ludvig Munthe, MD, PhD, Institute of Immunology, Oslo University Hospital, Rikshospitalet
Prof. Jan Delabie, Division of Pathology, Oslo University Hospital, The Norwegian Radium Hospital
Prof. Ola Myklebost, Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital
Prof. Terje Espevik, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim
Prof. Gunhild Mælandsmo, Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital
Dr. Espen Thiis Evensen, Department of Medicine, Oslo University Hospital, Rikshospitalet
Prof. Fahri Saatcioglu, Faculty of Mathematics and Natural Sciences, Department of Molecular Biosciences, University of Oslo
Prof. David Bilder, University of California, Berkeley, USA
Prof. Sophie D. Fosså, Division of Surgery and Cancer Medicine, Oslo University Hospital, The Norwegian Radium Hospital
Prof. Erik Schrumpf, Department of Medicine, Oslo University Hospital, Rikshospitalet
Professor Stephen Chanock, NIH, National Cancer Institute, USA
Prof. Terje Johansen, Institute of Medical Biology, University of Tromsø
Dr. Grethe Skretting, Department of Hematology, Oslo University Hospital, Ullevål
Professor Silvia Corvera, University of Massachusetts, Worcester, USA
Dr. Sigbjørn Smeland, Head of Division of Surgery and Cancer Medicine, Oslo University Hospital, The Norwegian Radium Hospital Kirsten Sundby Hall, MD, PhD, Head of Sarcoma Programme, Oslo University Hospital, The Norwegian Radium Hospital
International collaboration 2010 Ash A. Alizadeh, MD, PhD, Stanford University, USA Prof. Peter Andrews, University of Sheffield, England Professor Eric Baehrecke, University of Massachusetts, Worcester, USA Prof. H. Barth, University of Ulm, Germany
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COLLABORATIONS
Prof. Bo van Deurs, University of Copenhagen, Denmark Professor Ivan Dikic, Goethe University, Frankfurt, Germany
Prof. Ron Levy, MD, Stanford University, USA Professor Urban Lendahl, Karolinska Institute, Stockholm, Sweden Prof. R. Massol, Harvard University, Boston, USA
Prof. Stephan Dirnhofer, MD, Swiss Group for Clinical Cancer Research, Switzerland
Professor Katherine McGlynn, NIH, National Cancer Institute, USA
Dr. Kim Ekroos, Finland Prof. Hanna Fares, The University of Arizona, USA Dr. Jude Fitzgibbon, Institute of Cancer, Queen Mary School of Medicine and Dentistry, London, UK
Prof. Fredrik Mertens, Dept Clinical Genetics, University of Lund, Sweden Dr. Jim Norman, The Beatson Institute for Cancer Research, Glasgow, UK Professor Marco Novelli, University College London, England
Prof. V. Gerke, University of Münster, Germany Jonathan Irish, PhD, Stanford University, USA Dr. Johanna Ivaska, University of Turku, Finland Prof. Olli Kallioniemi, Finnish Institute for molecular medicine, Helsinki, Finland Prof. Tom Kirchhausen, Harvard University, Boston, USA
Prof. Yasufumi Omori, Department of Pathology, University of Akita, Japan Prof. Jacek Otlewski, University of Wroclaw, Inst. Mol. Biol. and Biochem, Poland
Dr. Ewa Rajpert-De-Meyts, University Dept Growth and reproduction, The National hospital, Copenhagen, Denmark Lucia E. Rameh, PhD, Boston Biomedical Research Institute, USA Dr. Monika Slominska-Wojewodzka, Department of Molecular Biology, University of Gdansk, Poland Prof. Louis M. Staudt, MD, PhD, Head of The Leukemia and Lymphoma Molecular Profiling Project (LLMPP), National Cancer Institute, USA Prof. Manuel Teixeira, Portuguese Oncology Institute, Porto, Portugal Dr. Urs Utiger, MD, Swiss Group for Clinical Cancer Research, Switzerland Associate Professor Ai Yamamoto, Columbia University, New York, USA
Dr. Ruth Palmer, University of Umeå, Sweden Professor, Director Piero Picci, Lab Experimental Oncology, Rizzoli Ortopedic Institute, Bologna, Italy
Dr. Pavel Krejci, Medical Genetics Institute, Cedars-Sinai Medical Center, LA, USA
COLLABORATIONS
51
MEDIA
Dagbladet about the work of researcher Guro E. Lind Newspapers - New method to reveal cancer (Bildet på side 4 i fil artikel)
Cover story in Dagbladet about the work project of researcher May 201, portrays the biomarker from the Lothe Guro lab (in E. Lind from Lothe lab - New method to reveal cancer
e har utviklet en ny metode for å oppdage tykktarmskreft før den The article from 1 May 2010, portrays the bioetoden kan også brukes til å skreddersy behandlingen.
Aftenposten interview with Harald Stenmark on the incredible story about the immortal Henrietta Lacks
mikroskopet, der de sprer seg fint utover, forteller Stenmark.
Interview with Harald Stenmark in Aftenposten on 16 July 2010 (in Norwegian only)
– I dag vil alltid cellelinjer anonymiseres, og det må skaffes samtykke hvis vevsprøver skal brukes i forskning.
Media marker project from the Lothe lab (in Norwegian
– Snart 60 år etter sin død lever Henrietta Lacks fortsatt. Hun dyrkes i laboratorier verden over, Newspapers inkludert Norge, og kan leve i det uendelige. Hen– Norske forskere har rietta fikk ikke vite at legene tok celleprøver av utviklet en ny metode for å Cover story in Dagbladet about the work of researcher Lind Celler som gjorde det mulig å utvikle poliohenne. oppdage tykktarmskreft før Guro E. from Lothe lab - New method to dødelig. reveal cancer (Bildet på side vaksinen, 4 i fil og som startet en medisinsk revolusjon. den blir Metoden med Dagbladet artikel) kan også brukes til å skredThe article from 1 May 201, portrays the biomarker project from the Lothe lab (in – Tilbake på Radiumhospitalet i Oslo er det bilder dersy behandlingen. Norwegian only) av fargerike Hela-celler som pryder forsidene på Guro E. Lind. flere - Norske forskere har utviklet en ny metode for å oppdage tykktarmskreft før den av de medisinske tidsskriftene professor (Foto: Ola Sæther) blir dødelig. Metoden kan også brukes til å skreddersy behandlingen. Harald Stenmark har i hyllene på sitt kontor. Han Researcher Guro leder Seksjon for biokjemi ved sykehusets forskningsinstitutt. Her bruker de HeLa-celler i stor stil. only).
Sæther)
– Jeg vet ikke om noen annen cellelinje der man kjenner til historien og personen bak, sier professor Harald Stenmark ved Radiumhospitalet. 8 NYHETER
Lørdag 17. juli 2010
9
NYHETER
Lørdag 17. juli 2010
Forfatter Rebecca Skloot (t.h.) kom tett på Henrietta Lacks’ barn under det ti år lange arbeidet med boken, og hun fikk et spesielt nært forhold til Henriettas datter, Deborah Lacks. FOTO: REBECCA SKLOOT
Henrietta Lacks
HeLa-celler dyrkes i et medium bestående av aminosyreløsning tilsatt serum fra kalveblod. Når væsken holder seg rødfarget, viser det at surhetsgraden ikke blir for lav, men holder seg på pH-verdi 7. Denne celleflasken er merket Hela P, noe som betyr at disse cellene kommer fra en cellebank i Paris.
Født: Loretta Pleasant, 1. august 1920 i Roanoke, Virginia, USA. Skiftet navn til Henrietta, kallenavn Hennie. Ektefelle: David Lacks (1915– 2002), hennes fetter. Barn: Lawrence Lacks (1935), Elsie Lacks (1939), David «Sonny» Lacks jr. (1947), Deborah (Lacks) Pullum (1949) og Joseph Lacks (1950). Yrke: Tobakksdyrker Død: 4. oktober 1951, 31 år gammel, i Baltimore, Maryland, USA. Gravlagt i en umerket grav i Lackstown, Virginia.
fakta
erview with Harald Stenmark on the incredible story ortal Henrietta Lacks (Bilde: settes sammen fra 2 filer)
ald Stenmark in Aftenposten on 16 July 2010 (in Norwegian only)
– HeLa-celler er de mest studerte cellene i verden. Vi vet mye om dem, og derfor er de enkle å jobbe med. De er veldig nyttige og er prototypen på hvordan celler fungerer. De deler seg fort og kan vokse i det uendelige. Og de ser pene ut i
n død lever Henrietta Lacks fortsatt. Hun dyrkes i laboratorier Professor Ragnhild A. Lothe leder Avdeling ert Norge, og kan leve i det uendelige. Henrietta fikk ikke vite at for kreftforebygging vedpoliovaksinen, Radiumhospitalet der Researcher Guro ver av henne. Celler somE. gjorde det mulig å utvikle Lind. (Foto: Ola Sæther) forskerne har identifisertbiomarkørene. Her sammedisinsk revolusjon. hospitalet i Oslo er det bilder fargerike Hela-celler som pryder menav med doktorgradsstudent Kim Andresen. v de medisinske tidsskriftene professor Stenmark har i (Foto: ØisteinHarald Norum Monsen) with Harald Stenmark on the incredible story or. Han leder Seksjon forAftenposten biokjemi vedinterview sykehusets about the immortal Henrietta Lacks (Bilde: settes sammen fra 2 filer) Her bruker de HeLa-celler i stor stil. de mest studerte cellene i verden. Vi vet mye om dem, og derfor er
52
Interview with Harald Stenmark in Aftenposten on 16 July 2010 (in Norwegian only)
MEDIA Snart 60 år etter sin død lever Henrietta Lacks fortsatt. Hun dyrkes i laboratorier verden over, inkludert Norge, og kan leve i det uendelige. Henrietta fikk ikke vite at legene tok celleprøver av henne. Celler som gjorde det mulig å utvikle poliovaksinen, og som startet en medisinsk revolusjon.
Cellelinjer HeLa-celler vokser og deler seg langt kraftigere og raskere enn andre FOTO: RADIUMHOSPITALET cellelinjer.
I laboratorier verden over dyrkes milliarder av celler etter Henrietta Lacks. Ofte pryder de forsidene av medisinske tidsskrifter.
Professor Harald Stenmark og avdelingsingeniør Anne Engen ved Seksjon for biokjemi på Radiumhospitalet sørger for sterile arbeidsforhold over laboratoriebenken når de jobber med HeLa-celler.
Professor Harald Stenmark og avdelingsingeniør Anne Engen ved Seksjon for biokjemi på Radiumhospitalet sørger for sterile arbeidsforhold over laboratoriebenken når de jobber med HeLaceller. (Foto: Ingar Haug Steinholt)
ELISABETH RANDSBORG INGAR HAUG STEINHOLT (foto)
I cellelaboratorium K05/040 på Radiumhospitalet i Oslo bor deler av Henrietta Lacks. Bak hvite dører, i et skap, ligger fire gjennomsiktige celleflasker merket Hela. Inkubatorskapet holder konstant en temperatur på 37 grader og et CO2-innhold på 5 prosent. Mediet cellene vokser i, fungerer best da. Fuktighet sørger for at cellene ikke tørker ut. HeLa-celler er nøysomme og lever i en aminosyreløsning tilsatt serum fra kalveblod: Litt næring, men også signalmolekyler, som gir beskjed til cellene om å holde seg i live. På denne måten blir Henrietta Lacks tatt vare på i laboratorier kloden rundt.
Kreft. Henrietta Lacks var en afroamerikansk kvinne født i 1920 i den amerikanske delstaten Virginia, der hun vokste opp hos sine besteforeldre. Hun giftet seg med sin fetter, David, og de flyttet etter hvert til Maryland, der de dyrket tobakk. De fikk fem barn sammen. Drøyt fire måneder etter at yngstemann var født, oppsøkte Henrietta det lokale sykehuset på grunn av blødninger og smerter i under-
«Fortsetter fra forrige side
livet. Det ble tatt prøver av livmorhalsen, og legene konstaterte at Henrietta hadde kreft. Åtte dager senere var hun til en ny undersøkelse, og denne gangen tok legen og kreftforskeren, George Otto Grey, flere vevsprøver fra Henriettas kreftsvulst, uten hennes viten og vilje. Det er fra disse vevsprøvene Hela-cellene stammer. Henrietta fikk behandling på sykehuset, men kreften lot seg ikke knekke. Hun døde i oktober 1951, 31 år gammel, og ble begravet i en umerket grav på familiegravstedet i Lackstown, Virginia. Dette kunne vært slutten på historien om Henrietta Lacks. Men cellene hennes ville det annerledes. For cellene til Henrietta oppførte seg på en måte legene aldri før hadde sett. I mange år hadde dr. Grey – og mange med ham – forsket og eksperimentert for å få menneskeceller til å overleve in vitro (utenfor kroppen), men uten å lykkes. Alle cellene døde etter et par omganger med celledeling. Men ikke cellene til Henrietta Lacks. De levde og delte seg, og de levde og delte seg i et sånt tempo og med en sånn kraft at de lever den dag i dag.
– HeLa-celler er de mest studerte cellene i verden. Vi vet mye om dem, og derfor er de enkle å jobbe med. De er veldig nyttige og er prototypen på hvordan celler fungerer. De deler seg fort og kan vokse i det uendelige. Og de ser pene ut i mikroskopet, der de sprer seg fint utover, forteller Stenmark. Forskerne på Radiumhospitalet bruker HeLa-celler blant annet til å få kunnskap om hvordan celledeling kan kontrolleres, siden ukontrollert celledeling gir opphav til kreft. – Signalmolekyler påvirker celledeling. Det er små proteiner som sier til cellene at de skal dele seg, og eventuelt også at de skal forflytte seg, altså spre seg til annet vev. Vi forsøker å få svar på hvordan dette henger sammen. Forskerne får fatt i HeLa-celler enten via andre kolleger, eller de kjøper dem fra cellebanker i Europa og USA. 2000 kroner for et reagensrør med frosne HeLa-celler sendt i posten og beskyttet av tørris, som holder nesten minus 80 grader. Én million Pene å se på. Tilbake på Radiumhospi- celler i et rør – på størrelse med et litt stort talet i Oslo er det bilder av fargerike Hela- knappenålshode når man sentrifugerer celler som pryder forsidene på flere av de dem ned. Revolusjon. Dr. Grey ønsket å holde medisinske tidsskriftene professor HarHenriettas identitet skjult, men han døpte ald Stenmark har i hyllene på sitt kontor. Et knappenålshode. Nøyaktig hva det cellene HeLa-celler etter de to første bok- Han leder Seksjon for biokjemi ved syke- er ved HeLa-cellene som gjør at de deler husets forskningsinstitutt. Her bruker de seg så fort og så kraftig, vet forskerne stavene i hennes for- og etternavn. Fordi de kunne leve og vokse i forsker- HeLa-celler i stor stil. fremdeles ikke. Etter hvert som teknolones laboratorier, kunne HeLa-celler brukes i et utall eksperimenter. Først og fremst var de grunnlaget for utviklingen av poliovaksinen få år etter Henriettas død. Senere er de blitt satt i masseproduksjon og Forfatter har vært dyrket og solgt Rebecca Skloot over hele kloden. De blir brukt i kreftforskning og AIDS-forskning. Blir brukt for å teste virkning av radioaktiv stråling og giftstoffer. De har vært sendt ut i verdensrommet for å teste påvirkning fra tyngdekraften, og de blir brukt i kosmetikkindustrien. Bare for å nevne noe. HeLa-cellene markerte starten på en medisinsk revolusjon og en biokjemisk milliardindustri. I løpet av de snart 60 årene som er gått siden Henrietta Lacks’ død, er det dyrket 50 millioner tonn HeLaceller, og hennes identitet er også etter hvert blitt kjent.
«Hvis forskere sender min mors celler gien har utviklet seg, finnes det mange udødelige cellelinjer – både fra mennes- til månen og injiserer dem med kjemikaker og dyr – men ingen som er så kraftig lier, hvordan kan hun da få hvile i fred», spurte Deborah, forteller Rebecca Skloot. som cellelinjen etter Henrietta Lacks. Hun har fulgt familien Lacks tett i ti år Fikk sjokk. For å få svar på hvorfor, kon- under arbeidet med boken, «The Immortaktet amerikanske forskere avdøde Hen- tal Life of Henrietta Lacks», som utkom riettas ektemann og barn tidlig på 1970- tidligere i år. – Boken er ikke bare historien om Hentallet. De ønsket DNA-prøver av dem for å prø- rietta og vevsprøvene som ble tatt fra henve å løse HeLa-gåten, men blodprøvene ga ne uten hennes samtykke. Det er også hisingen holdepunkter. Men de snudde ver- torien om hvordan dette har påvirket faden på hodet for ektemannen og barna, milien i ettertid. – Spesielt sønnene til Henrietta er oppsom først da fikk vite at Henrietta fortsatt rørt over at folk kjøper og selger morens levde i laboratorier verden rundt. – Det var et sjokk for dem, spesielt for celler, som jo var starten på en milliardindatteren Deborah, forteller den ameri- dustri, all den stund Henriettas egen famikanske journalisten Rebecca Skloot, som lie forblir fattige. Selv den dag i dag har de nå har utgitt en bok om Henrietta Lacks, ikke råd til å kjøpe seg helseforsikring, sier Skloot. hennes familie og hennes celler. Hun har opprettet en stiftelse, der deler – Familien Lacks hadde ikke mye skolegang, og ektemannen David visste knapt av overskuddet fra boksalget skal brukes hva en celle var. For dem var det noe scien- til helseforsikring for Henriettas barn og ce fiction-aktig over det hele, og de forsto skolegang for hennes etterkommere. ikke hva det innebar at morens celler fortsatt levde i laboratorier rundt om i verden. Etisk dilemma. – Men det er også en Spesielt datteren Deborah syntes dette var annen grunn til at jeg ville skrive denne skremmende. boken. Vi befinner oss i en tid da mediHun var redd for at hun skulle støte på sinsk forskning i stadig større grad er avkloninger av moren på gaten, og hun fryk- hengig av biologisk materiale, som Hentet at alt det forskerne gjorde med morens riettas celler. Men mange av de etiske celler, på en eller annen måte ville påføre spørsmålene som historien om Henriettas moren smerte. celler reiser, er fortsatt ubesvart: Bør folk
selv få bestemme hva som skjer med vevsprøvene sine etter at de er fjernet fra kroppen? Og hvem, hvis noen, skal kunne tjene penger på slike vevsprøver? – Henriettas historie er unik i den forstand at hennes identitet etter hvert ble knyttet til disse cellene, så vi vet nå hvem hun er. – Men det er mennesker bak hver eneste én av de milliarder av celler som oppbevares i cellebanker og laboratorier verden over. De fleste amerikanere har vevsprøver som blir brukt i forskning ett eller annet sted, men de færreste er klar over det, sier Rebecca Skloot.
Anonyme. – I dag vil alltid cellelinjer anonymiseres, og det må skaffes samtykke hvis vevsprøver skal brukes i forskning. – Jeg vet ikke om noen annen cellelinje der man kjenner til historien og personen bak, sier professor Harald Stenmark ved Radiumhospitalet. – Kjente du til Henrietta Lacks? – Jeg visste det var en person med det navnet som skjulte seg bak HeLa-cellene, men jeg kjente ikke til historien hennes. Jeg har ikke tenkt så mye over dette før, men det er jo litt spesielt. Så jeg kommer nok til å lese boken. – Det å få en cellelinje etter seg, er jo det nærmeste man kan komme udødelighet.
[email protected]
En cellelinje er betegnelsen på celler som kan dyrkes i laboratorier, og som kan dele seg uendelig mange ganger. De oppbevares nedfrosset i flytende nitrogen, som holder en temperatur på minus 196 grader. Ved bruk tines cellene og oppbevares i et medium bestående av aminosyreoppløsning og serum fra kalveblod. Disse stoffene gir cellene næring, men også signaler om at cellene skal holde seg i live. HeLa-celler er den første menneskelige cellelinje. I dag finnes det tusenvis av cellelinjer fra både mennesker, dyr og planter. Ingen cellelinje er så mye brukt innen medisinsk forskning som HeLa-celler.
fakta
Rolf Skotheim’s project selected for Cancer Society advertisement
Illustration by Camilla Raiborg in VG article about cancer treatment 14 14
– Jeg arbeider med å finne bedre metoder for å diagnostisere og behandle tykktarmskreft. Forskningspengene jeg har fått fra Kreftforeningen gjør det mulig å få gode resultater enda raskere.
Oslo Cancer Cluster supplement to Aftenposten covers CCB research on biomarkers
Lørdag 16. oktober 2010
Lørdag 16. oktober 2010
Slik skal kreft behandles b
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PÅ NORGESBESØK: Doug Ulman på toppen av nye Holmenkollen.
Foto: nyebilder.no
I 2009 ga vi 167 millioner kroner slik at forskerne kan fortsette innsatsen for å nå vårt store felles mål – at færre skal få kreft, at flere skal overleve og bli friske, og at de som må leve med sykdommen skal få et best mulig liv. Vi vet at forskning nytter. Takk til alle som støtter Kreftforeningens arbeid.
For første gang samarbeider to av verdens største legemiddelfirmaer for å utvikle et legemiddel fra grunnen av.
■ Diagnostiseringen ■ Diagnostiseringen blir alfa og omega i fremtidens kreftbehandling. Tester som er basert på enkle blodprøver vil gi svar på om en pasient har kreft. ■ Når kreften er oppdaget vil man kartlegge de biologiske markørene hos pasienten både via blodprøve og prøver av svulsten. Forskerne får da de svarene de trenger for å kunne gi en behandling som er skreddersydd den enkelte. ■ Det vil komme flere avanserte dataprogrammer som kan analysere prøver fra pasienten. ■ Analyseprogrammet Target Now er et eksempel på hva det vil komme mer av. Ved å se på analyser av kreftsvulsten opp mot det som finnes av tilgjengelige studier og databaser, kan man finne frem til den behandlingen som ser mest lovende ut for akkurat denne pasienten.
■ De nye legemidlene ■ To ulike komponenter som er helt uten virkning hver for seg, kan bli en svært effektiv kur når de settes sammen. ■ Legemiddelselskapene har tradisjonelt hatt en enorm konkurranse seg imellom og mye hemmelighetskremmeri rundt egne komponenter. Nå mener mange at trenden går i retning av større grad av samarbeid mellom både legemiddelfirmaer og forskere. ■ Legemiddelindustrien må forandre måten den tenker på.
■ Immunterapi
Rolf Skotheim, forsker ved Oslo Universitetssykehus
Kampen mot kreft koster. Bli medlem i Kreftforeningen. Ring 07877 eller send sms Medlem til 2258 Se også www.kreftforeningen.no Medlemskap koster 275 kroner per år
■ Immunterapi ventes å bli den nye store behandlingsformen innen kreftbehandling. ■ Vaksinene går ut på å trigge kroppens eget immunforsvar til å angripe kreftcellene. De ulike kreftvaksinene som er under utprøving bruker ulike mekanismer i kroppen for å få til en slik stimulering av immunsystemet. ■ Mange ulike vaksiner er nå under utprøving over hele verden. ■ Immunterapivaksinen Provenge er den første som er ferdig, og den er nå lansert i USA.
■ Forskningen ■ Store paraplystudier som er et samarbeid mellom forskere i mange ulike land, vil kartlegge pasientens biologiske markører og samle funnene i store biobanker og databaser. ■ Slik vil man kunne identifisere mindre grupper av pasienter som har felles mutasjoner i gener, som reagerer likt på samme behandling eller lignende. ■ Denne kunnskapen vil danne grunnlaget for mindre studier hvor pasienter velges ut fordi de har ett eller flere biologiske fellestrekk. ■ Forskningen vil derfor gå bort fra store randomiserte studier med hundrevis av pasienter. Ved å finne akkurat de riktige pasientene, er det nok med langt færre pasienter for å påvise effekt av behandlingen.
■ Tradisjonell behandling ■ Strålebehandling og cellegift forsvinner ikke med det første. ■ I mange tilfeller vil denne behandlingen være nødvendig for å skrumpe eller fjerne svulsten. ■ Mange av de nye behandlingene og legemidlene har som mål å gi tilleggsstøtte ved å trigge immunsystemet eller å stoppe videre vekst. ■ Flere nye legemidler som er under utvikling/utprøving tar også mål av seg til å både knekke svulsten og hindre tilbakefall. Kilder: Professor Jonathan Knowles, Institutt for molekylær biologi, Helsinki. Professor og overlege Steinar Aamdal, ved seksjon for klinisk kreftforskning, Radiumhospitalet, Oslo universitetssykehus. Professor Jean-Pierre Armand, Institutt Claudius Regaud.
KREFTCELLE: Med mikroskop kan kreftforskerne studere kreftcellene. Her viser fargestoff hvor det er DNA (blått), muskelproteiner (rødt) og noen proteiner som forskerne studerer (grøntt).
The Norwegian Cancer Society awarded support to Rolf Skotheim’s project “Qualitative transcript variation in cancer” in 2010. In addition, Rolf Skotheim was selected to be presented in advertisements in major Norwegian newspapers in January 2011.
Foto: LINE MØLLER
– Starten på en ny trend
Rolf Skotheim, forsker og gruppeleder ved OUS, Radiumhospitalet, er en av flere hundre kreftforskere som har fått støtte fra Kreftforeningen til sine forskningsprosjekt.
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2017 HER ER VI I
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■ En enkel blodprøve vil kunne gi en omfattende analyse av kroppens biologiske markører og kan gi svar på om du har en av de store krefttypene. En test for prostatakreft ble lansert nå i oktober i USA. Tester for lungekreft, tykktarmskreft og brystkreft er underveis i nær fremtid. ■ Får du positivt utslag på testen følges du opp for å finne ut hvor svulsten sitter og igangsetting av behandling. ■ Dette vil føre til at kreft oppdages tidligere og dermed hindrer spredning. Da vil operasjoner hvor svulsten fjernes i større grad kurere pasienten.
Foto: Dr. Camilla Raiborg, RADIUMHOSPITALET
2025 HER ER VI I
■ Behandlingen skreddersys til den enkelte. ■ Hvilken behandling og hvilke medisiner man skal bruke, blir bestemt ut omfattende analyser av blodprøver og kreftsvulsten. ■ Reaksjonen på behandlingen følges nøye fra uke til uke, og dersom man i løpet av kort tid ikke ser noen endring går man videre til neste medikament som man ser har potensial for akkurat denne pasienten.
■ I løpet av de neste ti årene vil immunbasert behandling være med på å revolusjonere kreftbehandlingen. ■ En av de aller viktigste årsakene til at noen overlever kreft, er at immunforsvaret deres reagerer og dreper kreftcellene. ■ Også for denne behandlingsformen er kartleggingen av de biologiske markørene viktige for å se hvilken av kroppens mekanismer det er mest hensiktsmessig å rette behandlingen mot. Kilde: Professor Jonathan Knowles, Institutt for molekylær biologi, Helsinki, og professor og overlege Steinar Aamdal, ved seksjon for klinisk kreftforskning, Radiumhospitalet, Oslo universitetssykehus.
The article in the Norwegian newspaper VG dated 16 October 2010 is in Norwegian only.
Tradisjonelt har legemiddelfirmaer holdt kortene tett for brystet. Konkurransen har vært knallhard, og det gjelder å være først med det siste. Men fremtidens legemidler krever nye måter å jobbe på, sier Gunnar Sæter, regional direktør i legemiddelselskapet MSD (heter Merck i USA). – Tidligere handlet alt om å drepe kreftcellene. Den moderne kreftbehandlingen går ut på å manipulere cellenes oppførsel, sier Sæter. Et nytt legemiddel vil ofte ha som mål å ta kontroll over de mekanismene som gjør at svulsten vokser. – Vi jobber med helt andre biologiske mekanismer og vi ser at sjansen for at et legemiddel skal virke er større dersom vi kombinerer to eller flere stoffer, sier Sæter.
Gir innsyn
De to legemiddelgigantene MSD/Merck og Astra Zeneca har derfor gått til et svært uvanlig skritt. De har gitt motparten innsyn i hvilke ulike stoffer og komponenter de jobber med. Deretter har de valgt ut to stoffer som de tror kan bli et kreftlegemiddel når de får virke sammen. – Jeg tror dette er starten på en ny trend, sier Sæter. Vesten har endelig fått øynene opp for det man har visst i kinesisk tradisjonell medisin, mener direktør ved Institutt Claudius Regaud i Frankrike, Jean-Philippe Armand. – To stoffer kan være
helt virkningsløse dersom de brukes hver for seg, men sammen setter du dem sammen så skjer det spennende ting, sier Armand. Stoffene vil også forsterke virkningen av hverandre. – 1+1+1=5, sier Armand. Administrerende direktør i Livestrong, Doug Ulman, roser legemiddelselskapene for å tenke nytt. – Vi må bort fra de stengslene som konkurranse og tradisjonelle strukturer gir. For å redde liv trenger vi at forskere og legemiddelselskaper samarbeider tettere, sier han.
Kreftnettverk
For å få innspill og bistand fra kreftforskere over hele verden fra et tidlig tidspunkt har MSD/Merck nå laget et kreftnettverk med 19 samarbeidspartnere i 16 land. Et av sentrene som er valgt ut er Oslo universitetssykehus. – Når vi har et lovende nytt stoff vil vi diskutere med forskere helt fra starten av hvordan vi best mulig skal angripe dette for at dette skal kunne bli et nytt legemiddel, sier Sæter. I andre sammenhenger vil det være aktuelt at samarbeidssentrene tester ut nye legemidler. – Vi vil tilføre samarbeidssentrene de ressursene de trenger for at det de skal gjøre for oss ikke går ut over samarbeid de har med andre, sier Sæter. Det er for tidlig å si om det kan bli aktuelt å teste ut det nye samarbeidslegemiddelet i Norge.
Fakta ■ Kreft har for første gang blitt dødsårsak nummer én i verden. ■ 70 prosent av dødsfallene i utviklingsland skyldes kreft. ■ 28 millioner mennesker lever med kreft i dag. I år 2030 er antallet tredoblet. ■ 33 000 mennesker får diagnosen hver dag. ■ Kreft koster verdenssamfunnet 895,2 milliarder i året, og kostnaden er stadig økende.
Interview with Ragnhild A. Lothe, April 2010, on colorectal cancer ( in Norwegian only)
Kilde: Doug Ulman, administrerende direktør i Livestrong.
– Bare 60 prosent av de som får tykktarmkreft lever etter fem år. Professor Ragnhild A. Lothe og hennes gruppe har funnet genmarkører som kan oppdage kreften mens den ennå kan kureres.
MEDIA
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Interview with CCB researcher on the importance of Australian findings of fluorescent corals with respect to cancer research
– Inne i en celle finnes en rekke forskjellige proteiner. Siden korallene som nå er oppdaget finnes i forskjellige farger, kan flere proteiner i en celle overvåkes samtidig ved at det festes forskjellig farget materiale fra korallene til flere forskjellige proteiner inne i cellen som forskeren studerer. – Forskerne bruker dette for å studere både friske og syke celler, så vi kan sammenlikne for å se hva som er galt i de syke cellene, sier Bache.
CCB’s Edgar Rivedal is appointed Chairperson of the IARC Scientific Council
Magazines and internet Kirsten Sandvig’s research high-lighted by the Norwegian Cancer Society Interview with researcher Kristi Bache in the newspaper Dagbladet on 14 August 2010 (in Norwegian only) – Kreftforsker ved Radiumhopsitalet, Kristi Bache, kjenner ikke til oppdagelsen fra Australia, men sier til Dagbladet at denne typen funn kan brukes til bedre å synliggjøre proteiner som forskere jobber med.
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MEDIA
The Norwegian Cancer Society has decided to focus on one research project each month, and the project obtaining attention in March 2010 is directed by Prof. Kirsten Sandvig. Sandvig’s research has been focused upon in an article published on the web site of the Cancer Society (in Norwegian), entitled The weapon must be fine-tuned more precisely to hit the target.
Edgar Rivedal from the Department of Cancer Prevention headed by Ragnhild A. Lothe at the Institute for Cancer Research, is appointed Chairperson of the Scientifc Council at the International Agency for Research on Cancer (IARC) for a four year period. In this connection an interview (in Norwegian only) with Edgar Rivedal was published in July 2010 on the homepage of The Research Council of Norway, entitled Ruster seg mot drastisk kreftøkning.
Findings in Nature Cell Biology paper from Stenmark’s group discussed on www.forskning.no
Interview with Ragnhild A. Lothe about the rare cancer type malignant peripheral nerve sheath tumors
CCB Director Harald Stenmark awarded “Researcher of the Month” prize in March 2010
A recent article from Harald Stenmark’s group published in Nature Cell Biology has attracted considerable attention. The paper is entitled “PtdIns(3) P controls cytokinesis through KIF13A-mediated recruitment of FYVE-CENT to the midbody” and is first-authored by Antonia Sagona.
The Strategic Initiative on Cancer Research from the Research Council of Norway supports research on malignant peripheral nerve sheath tumors from the Lothe lab. The interview Gener avslører utsatte kreftpasienter was given by Ragnhild A. Lothe, in Norwegian only, June 2010, published on the RCN web pages.
The South-Eastern Norway Regional Health Authority (Helse Sør-Øst) aims to profile ongoing excellent research in the region by calling special attention to a “Researcher of the month” – a prize that was introduced in January 2010.
The popular Norwegian research web site www.forskning.no has published an article (in Norwegian only) about the findings under the headline “Strict rules for cell division”, April 2010.
– Hvert år rammes ca ti nordmenn av nerveskjedekreft, som kan oppstå alle steder i kroppen hvor det finnes nerver. Det spesielle med kreftformen er at den oftere rammer unge voksne mellom 20 og 40 år sammenlignet med de fleste andre kreftformer. Nerveskjedekreft er også vanligst hos pasienter med den arvelige sykdommen nevrofibromatose. – I dag finnes det ikke noe standardisert behandlingstilbud utover kirurgi, og bare 30-40 prosent av pasientene overlever etter fem år.
The third researcher to receive this honor is CCB Director Harald Stenmark from the Department of Biochemistry at Oslo University Hospital. Research is an area of commitment for the SouthEastern Norway Regional Health Authority, which spends a total of 1.4 billion NOK on research every year. A news article (in Norwegian) is to be found on the web pages of South-Eastern Norway Regional Health Authority.
– Nå har forskere ved Oslo universitetssykehus funnet ut at pasienter med bestemte endringer i svulstens arvemateriale befinner seg i en høyrisikogruppe.
MEDIA
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ABOUT CCB
Facts 2010 Centre for Cancer Biomedicine
The board members are:
CCB was established in September 2007 as a Centre of Excellence appointed by the Research Council of Norway with the University of Oslo as host institution. The majority of our Centre is located at Oslo University Hospital, the Norwegian Radium Hospital. A consortium agreement regulates cooperation between the University of Oslo and Oslo University Hospital with the intention to make conditions favourable for fulfilling the scientific aims and strategic plans of CCB.
Prof. Sigbjørn Fossum - Chairman of the board, Dean of Research, Faculty of Medicine, University of Oslo
The Research Groups Seven research groups embracing an average of 130 people in 2010 constitute CCB. These seven groups are headed by Prof. Harald Stenmark, Prof. Ragnhild A. Lothe, Prof. Kirsten Sandvig, Prof. Erlend Smeland, Prof. Håvard Danielsen, Prof. Knut Liestøl, and Dr. Philos Antoni Wiedlocha. The group leaders meet once a month for scientific and strategic discussions.
Management The day-to-day management of CCB is performed by Director Harald Stenmark, Co-director Ragnhild A. Lothe, and Administrative coordinator Anette Sørensen.
The Board The Centre management reports to the CCB board having two members from the University of Oslo as well as two members from Oslo University Hospital. Board meetings are held twice a year. 56
ABOUT CCB
Prof. Anders Elverhøi, Dean of Research, Faculty of Mathematics and Natural Sciences, University of Oslo Prof. Karl-Erik Giercksky, Head of section for Surgical Oncology, Division of Surgery and Cancer Medicine, Oslo University Hospital Prof. Erlend Smeland, Director of Research and Development, Oslo University Hospital.
Scientific Advisory Board
The Scientific Advisory Board of CCB has five members: Professor Manuel Sobrinho-Simões, Head of Dept of Pathology, Medical Faculty of Porto & Director, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Portugal Professor Lena Claesson-Welsh, Head of Department of Genetics and Pathology, Uppsala University, Sweden Professor David J. Kerr, Professor of Cancer Medicine, University of Oxford, UK Professor Marja Jäättelä, Head of the Department, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark
Professor Olli Kallioniemi, Director of the Institute for Molecular Medicine Finland (FIMM), Nordic EMBL Partnership for Molecular Medicine, University of Helsinki & Director of Academy of Finland Centre of Excellence on Translational GenomeScale Biology, Helsinki, Finland. The Scientific Advisory Board supports our Centre with valuable input on strategy and science which helps us to achieve our goal of becoming one of Europe’s leading centres for cancer research. SAB’s third visit to CCB is planned for 11-12 May 2011.
Visiting Professors
CCB has three professors associated to the Centre. Professor Zena Werb, Department of Anatomy, University of California, San Francisco Professor Bo van Deurs, The Panum Institute, University of Copenhagen Professor Manuel Teixeira, Portugese Oncology Institute, Porto
Clinical Associates
CCB has two clinicians associated to the Centre: Harald Holte, Dr. med. Oslo University Hospital, The Norwegian Radium Hospital Prof. Arild Nesbakken Oslo University Hospital, Aker
Professors and researchers Postdocs PhD students Guest researchers Master students Technical staff Administrative staff Total
Figures 2010
7 3 6
2008 87 127
2009 89 138
2010 104 145
5 0 5
5 5 007 0
83 96
95 50 145
65 35 100
CCB staff – Development in manCategory Headcount In % years/headcount Principal Investigators 6 4 CCB staff – Development in man-years/headcount
Professors and researchers Postdocs 160 PhD students 140 Guest researchers 120 Master students 100 Technical staff Administrative staff 80 Total 60
27 29 36 3 7 32 5 145
19 20 25 2 5 Man-years 22 Headcount 3 Man-years 100 Headcount
40
Principal Investigators Professors and researchers Postdocs PhD students Guest researchers Master students Technical staff Administrative staff
2009 89 138
2010 104 145
Funding MNOK The Research Council of Norway 7,9 3% 4% The Norwegian Cancer Society 17,4 9,1 22International % South-Eastern Norway Regional Health Authority 9,5 Centre of Excellence 12,5 University of Oslo 5,8 Oslo University Hospital 24,5 The Radium Hospital Legacy Foundation 0,6
Since CCB’s inauguration in 2007, the number of man-years has increased with 25%. Our current infrastructure restricts further expansion of the 100 35 % Man-years centre, and we therefore plan only a modest ex80 Headcount 60 pansion during the years to come. CCB currently 40 Funding MNOK houses different nationalities.7,9 20 Research 15 The Council of Norway 17,4 9,1 9,5 12,5 5,8 24,5 0,6
2010
65 %
Gender distribution 2010 in % 35 %
Female Male 65 %
Recruitment of female scientists at PhD student and postdoc level is not considered a major obstacle in CCB. The real challenge lies in ensuring that the leaky pipeline of women through the academic hierarchy is stopped. CCB will actively support the promotion of talented female scientists through various means where the overall strategy is to create predictability and continuity, and thereby motivating women to stay in their current career path.
3%
22 %
4%
19 %
5% 2%
20 % 25 %
Principal Investigat Professors and res Postdocs PhD students Guest researchers Master students Technical staff Administrative staf
by position in %
19 %
5% 2%
20 % 25 %
4 2009 2010 19 Postdocs 20 CCB staff – Development in man-years/headcount PhD students 25 Gender distribution in % Guest researchers 2 160 Master students 5 140 Technical staff 22 120 Administrative staff 3
0 Norwegian Cancer Society The 2007 2008 2009 International South-Eastern Norway Regional Health Authority Gender distribution in % Centre of Excellence University of Oslo Oslo University Hospital The Radium Hospital Legacy Foundation
CCB staff
4 19 20 25 2 5 22 categorized 3
19 20 25 2 5 22 3 100
CCB staff categorized by position in %
20 Principal Investigators 0 2007 2008 Professors and researchers
2008 87 127
27 29 36 3 7 32 5 145
Principal Investigators
Guest researchers
Professors and researchers
Master students
Postdocs
Technical staff
PhD students
Administrative staff Funding in MNOK
Based on the fact that 65% of CCB members are female, an analysis 9,5 of the representation of fe12,5 9,1scientists in CCB was conducted male by CCB´s committee for gender equality. It identified one 5,8 problem area, namely the promotion of women to the highest scientific category, the project leader/ 17,4senior scientist level. Consequently, efforts have been made to address this issue, and we are hap24,5 py to report 7,9that major progress has been made. 0,6
Although there is only a small improvement at the CCB PI level (29% in 2007 increased to 33% in 2010), there is a very strong increase in female representation at the project leader/senior scientist level (13 % in 2007 vs 32 % in 2010).
Funding in MNOK (excluding in-kind Funding in MNOK contributions from our two host institutions) Principal Investigators
Professors and researchers 9,5 9,1 Postdocs PhD students Guest researchers Master students Technical staff 17,4 Administrative staff
7,9
The Research Counc
12,5 5,8
The Norwegian Canc International
South-Eastern Norw
Centre of Excellence University of Oslo
24,5
0,6
The Research Council of Norway
Centre of Excellence
The Norwegian Cancer Society
University of Oslo
International
Oslo University Hospital
South-Eastern Norway Regional
The Radium Hospital Legacy Foundation
Oslo University Hosp
The Radium Hospita
The of Norway TheResearch fundingCouncil situation for CCB
is good in the sense obtaining sufficient finanInternational cial resources to implement all its planned activiSouth-Eastern Norway Regional Health Authority ties. The Cancer thatNorwegian the centre hasSociety been
Centre of Excellence
Particularly the International funding has increased University of Oslo Oslo University Hospital dramatically since 2008
where the figure was 1 contributes with 9.1 MNOK. Similarly the contribution from the South-Eastern Norway Regional Health Authority has more than doubled from 2008 to 2010.
The Radium Foundation MNOK. InHospital 2010, Legacy International funding
The overall funding for CCB has increased with 18% from 2008 to 2010.
ABOUT CCB
57
CCB STAFF AND STUDENTS
58
Name
Position
Group
Nationality
Employer
Abrahamsen, Hilde
Project leader, Senior scientist
Stenmark
Norway
Oslo University Hospital
PhD
Ahlquist, Terje
Postdoc
Lothe
Norway
Oslo University Hospital
PhD
Ailte, Ieva
Master student/PhD student
Sandvig
Latvia
Oslo Univ. Hosp./University of Oslo
MSc
Alagaratnam, Sharmini
Postdoc
Lothe
Malaysia
Oslo University Hospital
PhD
Ali, Deeqa Ahmed Mohammed
Master student/PhD student
Lothe
Norway
Oslo University Hospital
MSc
Andersson, Sofia
Postdoc
Sandvig
Sweden
Oslo University Hospital
PhD
Andresen, Kim
PhD student
Lothe
Norway
University of Oslo
MSc
Bache, Kirsti Cecilie Grønvold
Postdoc
Stenmark
Norway
Oslo University Hospital
PhD
Bakkebø, Maren
PhD student
Smeland
Norway
Oslo University Hospital
MSc
Bakken, Anne Cathrine
Research fellow
Lothe
Norway
Oslo University Hospital
MSc
Bassols, Jose Maria
Computer specialist
Stenmark
Spain
Oslo University Hospital
Berg, Marianne
PhD student
Lothe
Norway
Oslo University Hospital
MSc
Bergan, Jonas
PhD student
Sandvig
Norway
Oslo University Hospital
MSc
Bergersen, Anne Gro
Technician
Stenmark
Norway
Oslo University Hospital
Bethge, Nicole
PhD student
Smeland
Germany
Oslo University Hospital
MSc
Brandal, Petter
Scientist
Danielsen
Norway
Oslo University Hospital
PhD
Brech, Andreas
Project leader, Senior scientist
Stenmark
Norway
Oslo University Hospital
PhD
Bredahl, May Kristin Lyamouri
Senior scientist
Smeland
Norway
Oslo University Hospital
PhD
Brekke, Helge
PhD student
Lothe
Norway
Oslo University Hospital
MSc
Bruun, Jarle
PhD student
Lothe
Norway
Oslo University Hospital
MSc
Cekaite, Lina
Postdoc
Lothe
Lithuania
Oslo University Hospital
PhD
Celestino, Ricardo
Guest PhD student
Lothe
Portugal
University of Porto
MSc
Christensen, Lene
Laboratory Assistant
Wiedlocha
Norway
Oslo University Hospital
Cordara, Gabriele
PhD student
Sandvig
Italy
University of Oslo
MSc
Dalbak, Hanne-Sofie Spenning
PhD student
Danielsen
Norway
University of Oslo
MSc
Danielsen, Håvard
P.I., Professor
Danielsen
Norway
Oslo University Hospital
PhD
Danielsen, Stine Aske
PhD student
Lothe
Norway
Oslo University Hospital
MSc
Dyve, Anne Berit
PhD student
Sandvig
Norway
Oslo University Hospital
MSc
Eide, Marianne Brodtkorb
PhD student
Smeland
Norway
Oslo University Hospital
MD
CCB STAFF AND STUDENTS
Academic title
Name
Position
Group
Nationality
Employer
Academic title
Eide, Peter
Master student
Lothe
Norway
Oslo University Hospital
Eiken, Hans Geir
Senior scientist
Lothe
Norway
Oslo University Hospital
Eknæs, Mette
Technician
Lothe
Norway
Oslo University Hospital
Engedal, Kim Nikolai
Postdoc
Sandvig
Norway
Oslo University Hospital
Engen, Anne
Technician
Stenmark
Norway
Oslo University Hospital
Ersvær, Elin
Research fellow
Danielsen
Norway
Oslo University Hospital
MSc
Forfang, Lise
Technician
Smeland
Norway
Oslo University Hospital
MSc
Frerker, Nadine
Postdoc
Sandvig
Germany
Oslo University Hospital
PhD
Fykerud, Tone
Master student/Research fellow
Lothe
Norway
Oslo University Hospital
MSc
Gedde, Ida
Laboratory Assistant
Stenmark
Norway
Oslo University Hospital
Gorunova, Ludmila
Scientist
Danielsen
Russia
Oslo University Hospital
PhD
Guriby, Marianne
Master student/Research fellow
Lothe
Norway
Oslo University Hospital
MSc
Haglund, Kaisa
Project leader, Senior scientist
Stenmark
Sweden
Oslo University Hospital
PhD
Haugom, Lisbeth
Research fellow
Danielsen
Norway
Oslo University Hospital
Haugsten, Ellen M.
Postdoc
Wiedlocha
Norway
Oslo University Hospital
PhD
Heim, Sverre
Group leader, Senior scientist
Danielsen
Norway
Oslo University Hospital
PhD
Hektoen, Merete
Technician
Lothe
Norway
Oslo University Hospital
MSc
Hessvik, Nina Pettersen
Postdoc
Sandvig
Norway
Oslo University Hospital
PhD
Hilden, Vera Irene
Technician
Smeland
Norway
Oslo University Hospital
MSc
Hoff, Andreas
Master student
Lothe
Norway
Oslo University Hospital
Honne, Hilde
Research fellow
Lothe
Norway
Inven2
MSc
Huse, Kanutte
PhD student
Smeland
Norway
Oslo University Hospital
MSc
Hveem, Tarjei Sveinsgjerd
PhD student
Danielsen
Norway
Oslo University Hospital
MSc
Høland, Maren
Master student/Research fellow
Lothe
Norway
Oslo University Hospital
MSc
Håvik, Annette Bentsen
PhD student
Danielsen
Norway
Oslo University Hospital
MSc
Iversen, Tore-Geir
Project leader, Senior scientist
Sandvig
Norway
Oslo University Hospital
PhD
Jenstad, Monica
Postdoc
Danielsen
Norway
Oslo University Hospital
PhD
Johannessen, May Elisabeth
Secretary
Norway
Oslo University Hospital
Karerwa, Jeanne D'Arc
Technician
Norway
Oslo University Hospital
Danielsen
PhD PhD
CCB STAFF AND STUDENTS
59
60
Name
Position
Group
Nationality
Employer
Katheder, Nadja Sandra
PhD student
Stenmark
Switzerland
Oslo University Hospital
MSc
Kildal, Wanja
PhD student/Postdoc
Danielsen
Norway
Oslo University Hospital
PhD
Kjeldby, Brage Braathen
Laboratory Assistant
Wiedlocha
Norway
Oslo University Hospital
Kjenseth, Ane Hansen
PhD student
Lothe
Norway
Oslo University Hospital
Kjæreng, Marna Lill
Technician
Danielsen
Norway
Oslo University Hospital
Klokk, Tove Irene
Postdoc
Sandvig
Norway
Oslo University Hospital
PhD
Kolberg, Matthias
Scientist
Lothe
Norway
Oslo University Hospital
PhD
Kraggerud, Sigrid M.
Scientist
Lothe
Norway
Oslo University Hospital
Dr. Philos
Kvalvaag, Audun Sverre
Master student
Sandvig
Norway
Oslo University Hospital
Kvamme, Linko Sigrid Izumi
Laboratory Assistant
Stenmark
Norway
Oslo University Hospital
Leithe, Edward
Project leader, Senior scientist
Lothe
Norway
Oslo University Hospital
Dr. Philos
Liestøl, Knut
P.I., Professor
Liestøl
Norway
University of Oslo
Dr. Philos
Lind, Guro Elisabeth
Project leader, Senior scientist
Lothe
Norway
Oslo University Hospital
Dr. Philos
Lingjærde, Ole Christian
Associate Professor
Liestøl
Norway
University of Oslo
PhD
Llorente Alicia
Project leader, Senior scientist
Sandvig
Spain
Oslo University Hospital
Dr. Philos
Lobert, Viola
PhD student
Stenmark
France
Oslo University Hospital
MSc
Lothe, Ragnhild A.
P.I., Professor
Lothe
Norway
Oslo University Hospital
Dr. Philos
Lukoseviciute, Simona
Master student
Sandvig
Lithuania
Oslo University Hospital
Løvf, Marthe
PhD student
Lothe
Norway
University of Oslo
MSc
Malerød, Lene
Postdoc
Stenmark
Norway
Oslo University Hospital
PhD
Martinsen, Janne
Laboratory Assistant
Stenmark
Norway
Oslo University Hospital
Merok, Marianne Aarstad
PhD student
Lothe
Norway
Oslo University Hospital
MD
Micci, Francesca
Scientist
Danielsen
Norway
Oslo University Hospital
PhD
Mjøen, Linda Uv
Advisor
Norway
Oslo University Hospital
Musa, Nagham
PhD student
Sandvig
Sweden
Oslo University Hospital
MSc
Myklebust, June Helen
Project leader, Senior scientist
Smeland
Norway
Oslo University Hospital
PhD
Myrann, Anne Grethe
Technician
Sandvig
Norway
Oslo University Hospital
Nadratowska-Wesolowska,Beata
Postdoc
Wiedlocha
Poland
Oslo University Hospital
PhD
Nesheim, John Arne
Head of developement
Danielsen
Norway
Oslo University Hospital
MSc
CCB STAFF AND STUDENTS
Academic title
MSc
Name
Position
Group
Nationality
Employer
Academic title
Nezis, Ioannis
Postdoc
Stenmark
Greece
Oslo University Hospital
PhD
Nielsen, Birgitte
Postdoc
Danielsen
Norway
Oslo University Hospital
PhD
Nilsen, Gro
Research fellow
Liestøl
Norway
University of Oslo
MSc
Nome, Torfinn
PhD student
Lothe
Norway
Oslo University Hospital
MSc
Nybøen, Åsmund
Head of lab
Danielsen
Norway
Oslo University Hospital
Nymark, Carl-Martin
Master student
Sandvig
Norway
Oslo University Hospital
Nyqvist, Kaja Beate
PhD student
Danielsen
Norway
Oslo University Hospital
MSc
Oksvold, Morten
Postdoc
Smeland
Norway
Oslo University Hospital
PhD
Olsnes, Sjur
Professor emeritus
Wiedlocha
Norway
Oslo University Hospital
MD, PhD
Oppelt, Angela
PhD student
Wiedlocha
Germany
Oslo University Hospital
MSc
Paulo, Paula
Guest PhD student
Lothe
Portugal
Portuguese Oncology Inst.
MSc
Pedersen, Anne-Mari Gjestvang
Technician
Sandvig
Norway
Oslo University Hospital
MSc
Pedersen, Nina Marie
Postdoc
Stenmark
Norway
Oslo University Hospital
PhD
Phuyal, Santosh
Master student
Sandvig
Nepal
Oslo University Hospital
Platta, Harald
Postdoc
Stenmark
Germany
EMBO
PhD
Pradhan, Manohar
PhD student
Danielsen
Nepal
Oslo University Hospital
MD
Pretorius, Maria
Administrative head
Danielsen
Norway
Oslo University Hospital
MSc
Pust, Sascha
Postdoc
Sandvig
Germany
Oslo University Hospital
PhD
Raiborg, Camilla
Project leader, Senior scientist
Stenmark
Norway
Oslo University Hospital
PhD
Rivedal, Edgar
Group leader, Senior scientist
Lothe
Norway
Oslo University Hospital
Dr. Philos
Rodahl, Lina W.
PhD student
Stenmark
Norway
Oslo University Hospital
MSc
Roxrud, Ingrid
Postdoc
Stenmark
Norway
Oslo University Hospital
PhD
Rusten, Tor Erik
Project leader, Senior scientist
Stenmark
Norway
Oslo University Hospital
PhD
Rødland, Einar
Scientist
Liestøl
Norway
University of Oslo
PhD
Rønning, Eva
Head technician
Stenmark
Norway
Oslo University Hospital
Sagona, Antonia
PhD student
Stenmark
Greece
Oslo University Hospital
MSc
Sandvig, Kirsten
P.I., Professor
Sandvig
Norway
Oslo University Hospital
Dr. Philos
Schink, Kay Oliver
Postdoc
Stenmark
Germany
Oslo University Hospital
PhD
Sem Wegner, Catherine E.
PhD student
Stenmark
Norway
Oslo University Hospital
MSc
CCB STAFF AND STUDENTS
61
62
Name
Position
Group
Nationality
Employer
Silihagen, Mette
Research fellow
Danielsen
Norway
Oslo University Hospital
MSc
Sirnes, Solveig
PhD student
Lothe
Norway
Oslo University Hospital
MSc
Skarpen, Ellen
Scientist
Stenmark
Norway
Oslo University Hospital
PhD
Skiple Skjerpen, Camilla
Postdoc
Wiedlocha
Norway
Oslo University Hospital
Dr. Philos
Skotheim, Rolf I.
Group leader, Senior scientist
Lothe
Norway
Oslo University Hospital
Dr. Philos
Skotland, Tore
Guest scientist
Sandvig
Norway
Oslo University Hospital
Dr. Philos
Sletten, Torunn
Research fellow
Wiedlocha
Norway
Oslo University Hospital
MSc
Smeland, Erlend Bremertun
P.I., Professor
Smeland
Norway
Oslo University Hospital
MD, PhD
Smestad, Marianne
Technician
Stenmark
Norway
Oslo University Hospital
Stenmark, Harald
P.I., Professor
Stenmark
Norway
Oslo Univ. Hosp./University of Oslo
Sudbø, Ingrid
Laboratory Assistant
Stenmark
Norway
Oslo University Hospital
Sveen, Anita
PhD student
Lothe
Norway
Oslo University Hospital
MSc
Szlachcic, Anna
Guest PhD student
Wiedlocha
Poland
University of Wroclaw
MSc
Sørensen, Anette
Administrative coordinator
Denmark
University of Oslo
Sørensen, Vigdis
Postdoc
Wiedlocha
Norway
Oslo University Hospital
PhD
Tcatchoff, Lionel
Postdoc
Sandvig
France
Oslo University Hospital
PhD
Thomassen, Gard O. Sundby
PhD student/Postdoc
Lothe
Norway
Inven2
PhD
Thoresen, Sigrid Bratlie
PhD student
Stenmark
Norway
Oslo University Hospital
MSc
Thorsen, Jim
Postdoc
Danielsen
Norway
Oslo University Hospital
PhD
Torgersen, Maria Lyngaas
Postdoc
Sandvig
Norway
Oslo University Hospital
PhD
Vedeld, Hege Marie
Master student
Lothe
Norway
Oslo University Hospital
Vietri, Marina
PhD student
Stenmark
Italy
Oslo University Hospital
MSc
Wesche, Jørgen
Project leader, Senior scientist
Wiedlocha
Norway
Oslo University Hospital
Dr. Philos
Wiedlocha, Antoni
Group leader, Senior scientist
Wiedlocha
Poland
Oslo University Hospital
Dr. Philos
Wæhre, Håkon
Medical consultant
Danielsen
Norway
Oslo University Hospital
MD, PhD
Yohannes, Zeremariam
Technician
Lothe
Norway
Oslo University Hospital
Yri, Olav Erich
Phd student
Smeland
Norway
Oslo University Hospital
MD
Zhen, Yan
PhD student/Postdoc
Wiedlocha
China
Oslo University Hospital
PhD
Ågesen, Trude Holmeide
PhD student
Lothe
Norway
Oslo University Hospital
MSc
CCB STAFF AND STUDENTS
Academic title
Dr. Philos
CCB would like to thank the f and support:
SPONSORS 2010 CCB would like to thank the following funding organizations and sponsors for their valuable financial commitment and support:
Logo
CCB would like to thank the following fundin and support:
Radiumhospitalets Legater
SPONSORS
63
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Phone: +47 22 78 18 27
[email protected] www.cancerbiomed.net
Foto | Øystein H. Horgmo, Foto- og videotjenesten, UiO/OUS
ANNUAL REPORT 2010 64
CCB
Centre for Cancer Biomedicine Oslo University Hospital Norwegian Radium Hospital Montebello N-0310 Oslo Norway
