Prof. R. Versteeg PhD

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Prof. R. Versteeg PhD

Position
Full Professor
Main activities
Research, Other
Specialisation
Molecular Biology of Childhood Tumors
Focus of research

Focus of research are firstly the molecular biology and genetic defects of several pediatric tumors (neuroblastoma, medulloblastoma and rhabdomyosarcoma) and secondly the overall organization of gene expression of the human genome. Both research lines are supported by a strong bioinformatics and systems biology approach. The pediatric oncology research ranges from analysis of patient material for prognostic research, via fundamental research on molecular pathways and pathologic mechanisms, to validation of targets for novel drugs. In general, we search for genes mutated in tumors of pediatric cancer patients and subsequently try to reconstruct the molecular pathways in which these genes function. This is done by inducible expression of transgenes in cell lines, followed by mRNA profiling using microarrays or SAGE. Expression constructs include dominant negative genes and siRNA constructs. In parallel, large tumor series are analyzed by microarrays. Bioinformatic approaches and further wet-lab approaches are used to reconstruct the molecular pathways and their complex interactions. Pathways studied include the cell cycle, the N-myc and Delta-Notch pathways and pathways of many homeobox proteins like Meis1, Phox2B, Msx1 and Otx1. RNA interference is used to validate components of these pathways for suitatable drug targets, or to validate available and experimental drugs, both in cell lines and mice. The data from all high trouhput mRNA analyses and the bioinformatic tools developed to analyse them, are also used in the project to analyse the expression profile of the human genome. In this program we analyze the mechanisms and principles underlying our observation that the human genome is subdivided in domains of high and low gene expression.

Key publications
  • van Groningen Tim, Koster Jan, Valentijn Linda J., Zwijnenburg Danny A., Akogul Nurdan, Hasselt Nancy E., Broekmans Marloes, Haneveld Franciska, Nowakowska Natalia E., Bras Johannes, van Noesel Carel J. M., Jongejan Aldo, van Kampen Antoine H., Koster Linda, Baas Frank, van Dijk-Kerkhoven Lianne, Huizer-Smit Margriet, Lecca Maria C., Chan Alvin, Lakeman Arjan, Molenaar Piet, Volckmann Richard, Westerhout Ellen M., Hamdi Mohamed, van Sluis Peter G., Ebus Marli E., Molenaar Jan J., Tytgat Godelieve A., Westerman Bart A., van Nes Johan, Versteeg Rogier Neuroblastoma is composed of two super-enhancer-associated differentiation states Nature genetics 2017;49 (8):1261-1266 [PubMed]
  • Valentijn Linda J., Koster Jan, Zwijnenburg Danny A., Hasselt Nancy E., van Sluis Peter, Volckmann Richard, van Noesel Max M., George Rani E., Tytgat Godelieve A. M., Molenaar Jan J., Versteeg Rogier TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors Nature genetics 2015;47 (12):1411-+ [PubMed]
  • Eleveld Thomas F., Oldridge Derek A., Bernard Virginie, Koster Jan, Daage Leo Colmet, Diskin Sharon J., Schild Linda, Bentahar Nadia Bessoltane, Bellini Angela, Chicard Mathieu, Lapouble Eve, Combaret Valérie, Legoix-Né Patricia, Michon Jean, Pugh Trevor J., Hart Lori S., Rader JulieAnn, Attiyeh Edward F., Wei Jun S., Zhang Shile, Naranjo Arlene, Gastier-Foster Julie M., Hogarty Michael D., Asgharzadeh Shahab, Smith Malcolm A., Guidry Auvil Jaime M., Watkins Thomas B. K., Zwijnenburg Danny A., Ebus Marli E., van Sluis Peter, Hakkert Anne, van Wezel Esther, van der Schoot C. Ellen, Westerhout Ellen M., Schulte Johannes H., Tytgat Godelieve A., Dolman M. Emmy M., Janoueix-Lerosey Isabelle, Gerhard Daniela S., Caron Huib N., Delattre Olivier, Khan Javed, Versteeg Rogier, Schleiermacher Gudrun, Molenaar Jan J., Maris John M. Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations Nature genetics 2015;47 (8):864-871 [PubMed]
  • Molenaar Jan J., Koster Jan, Zwijnenburg Danny A., van Sluis Peter, Valentijn Linda J., van der Ploeg Ida, Hamdi Mohamed, van Nes Johan, Westerman Bart A., van Arkel Jennemiek, Ebus Marli E., Haneveld Franciska, Lakeman Arjan, Schild Linda, Molenaar Piet, Stroeken Peter, van Noesel Max M., Ora Ingrid, Santo Evan E., Caron Huib N., Westerhout Ellen M., Versteeg Rogier Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes Nature 2012;483 (7391):589-U107 [PubMed]
  • Versteeg Rogier CANCER Tumours outside the mutation box Nature 2014;506 (7489):438-439 [PubMed]
All Publications
Research programmes

Prof. R. Versteeg PhD (Regulatory networks in cancer)

The research program focuses on the elucidation of the regulatory networks underlying pathogenesis of the childhood tumors neuroblastoma, medulloblastoma and rhabdomyosarcoma. Affymetrix profiling was performed on large series of these tumors. Genes with a role in these tumors are systematically switched on or switched off in cell lines by inducible cDNA or siRNA expression (Tet-on system). RNA from time-courses of these cell lines was analyzed by Affymetrix expression arrays, usually in triplo and of different clones. Downstream pathways of about 15 genes were analyzed in this way. Elaborate bioinformatics programs were generated to identify downstream networks of the manipulated genes and to relate these data to the expression patterns observed in the tumor series. As each of the manipulated genes (like MYCN, NOTCH, EZH2, MSX1, CDK2) appear to regulate expression of hundreds of downstream genes, the emerging networks appear to be complex. The networks are further analyzed by silencing of transcription factors and other key genes in the networks. This requires an increase in the number of gene manipulations. For this purpose we have started to silence gene expression by lentivirally encoded siRNAs (TRC library). Over 15 genes were efficiently silenced this way and their downstream pathways are currently analyzed by microarrays. 

 

Theme: Oncology

Faculty
J.J.B. Koster PhD
L.J. Valentijn PhD

Postdocs
M. Hamdi PhD
W.J. van Nes PhD
E.M. Westerhout PhD

Others
P. Molenaar
D.A. Zwijnenburg BEng

Prof. H.N. Caron MD PhD (Paediatric Oncology; biology and clinical)

Current PhD Candidates
  • M.C. Commandeur
  • A. Hakkert
Current research funding
  • AMC
  • Europese Unie
  • KWF Kankerbestrijding
  • Prinses Maxima Centrum voor kinderoncologie B.V.
  • ZonMw