Research interest
This research group is using functional genomic technologies for the identification of novel targets for the development of anticancer drugs. We are developing our screening systems along three lines: 1. the identification of novel players in important cellular pathways deregulated in cancer, 2. the elucidation of the mechanism of drug action and resistance and 3. the identification of (synthetic or synergistic) lethal interactions to identify genotype specific drug targets.
Over the last years my group has invested in the generation of tools to perform functional genetic screens with special emphasis on loss-of-function cell based screens. To facilitate loss of function genetic screens we have developed large collections of shRNA knockdown vectors, targeting large numbers of both human and mouse genes. The development of these technologies has opened up the possibility to perform large scale mammalian somatic genetics.
Apart from the construction of large collections of shRNA vectors, my lab has a strong focus on the development of novel technologies using RNAi for gene identification. One of these technologies, shRNA bar code screening, although still under development, has already demonstrated its power in numerous biological screening systems. We have further extended our technology platform with siRNA and esiRNA technologies and will apply these technologies to identify novel components of important cellular networks that are affected or deregulated in human cancer. The goal of these projects is to identify novel drug targets beyond the classical oncogenes and tumor suppressor genes with particular emphasis on those targets that can be used in a tumor specific window. Examples of the use of these technologies are the identification of five novel genes that act in the p53 pathway and upon activation result in a bypass of a p53 mediated cell cycle arrest and the finding that intrinsic DNA damage signalling, characteristic for tumor cells, mediates the outcome of a novel type of drugs based on their capacity to re-activate the p53 pathway.
At this moment a considerable part of our efforts is aimed at the development and implementation of biological screens based on (multiple) complex phenotypes. An integral part of this effort is the realization of an automated high content screening platform with state-of-the-art image analysis software, database development and statistical analysis, integrated with bioinformatics. We believe that the combination of loss-of-function technologies with the ability to explore more complex phenotypes on a single cell level will significantly enhance the identification of novel targets and further insights in the molecular mechanisms leading to cancer.
Key publications
Brummelkamp, T. R., Fabius, A. W., Mullenders, J., Madiredjo, M., Velds, A., Kerkhoven, R. M., Bernards, R., and Beijersbergen, R. L. (2006). An shRNA barcode screen provides insight into cancer cell vulnerability to MDM2 inhibitors. Nat Chem Biol 2, 202-206.
Brummelkamp, T.R., Berns, K., Hijmans, E.M., Mullenders, J., Fabius, A., Heimerikx, M., Velds, A., Kerkhoven, R.M., Madiredjo, M., Bernards, R. and Beijersbergen, R.L. (2005). Functional identification of cancer-relevant genes through large-scale RNA interference screens in mammalian cells. In: Cold Spring Harbor Symposia on Quantitative Biology Vol. 69: Epigenetics. p 439-445.
Berns, K., Hijmans, E.M., Mullenders, J., Brummelkamp, T.R., Velds, A., Heimerikx, Kerkhoven, R. M., Madiredjo, M., Nijkamp, W., Weigelt, B., Agami, R., Ge, W., Cavet, G., Linsley, P.S., Beijersbergen, R.L. and Bernards, R. (2004). A large-scale RNAi screen in human cells identifies new components of the p53 pathway. Nature, 428, 431-437.
Hahn, W. C., Counter, C. M., Lundberg, A. S., Beijersbergen, R. L., Brooks, M. W., and Weinberg, R. A. (1999). Creation of human tumour cells with defined genetic elements. Nature 400, 464-468.
Hahn, W. C., Stewart, S. A., Brooks, M. W., York, S. G., Eaton, E., Kurachi, A., Beijersbergen, R. L., Knoll, J. H., Meyerson, M., and Weinberg, R. A. (1999). Inhibition of telomerase limits the growth of human cancer cells. Nat Med 5, 1164-1170.
Counter, C. M., Hahn, W. C., Wei, W., Caddle, S. D., Beijersbergen, R. L., Lansdorp, P. M., Sedivy, J. M., and Weinberg, R. A. (1998). Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization. Proc Natl Acad Sci U S A 95, 14723-14728.
Meyerson, M., Counter, C. M., Eaton, E. N., Ellisen, L. W., Steiner, P., Caddle, S. D., Ziaugra, L., Beijersbergen, R. L., Davidoff, M. J., Liu, Q., et al. (1997). hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 90, 785-795.
Reviews
Bernards, R., Brummelkamp, T. R., and Beijersbergen, R. L. (2006). shRNA libraries and their use in cancer genetics. Nat Methods 3, 701-706.
List of relevant websites
http://www.screeninc.nl
Biographic sketch
Roderick Beijersbergen did his doctoral research in the lab of René Bernards at the Netherlands Cancer Institute in Amsterdam where he studied the control of the cell cycle by the retinoblastoma gene family. He received his Ph.D from the University of Utrecht in 1995. He then joined the group of Robert Weinberg at the Whitehead Institute in Cambridge, USA for his postdoctoral training. He was involved in the identification of the catalytic component of telomerase, hTERT, in human cells and studied the role and regulation of hTERT expression in the transformation of normal cells to tumor cells. In 1999 he returned to the Netherlands Cancer Institute as an AvL fellow where he continued to work on the regulation of the expression of hTERT.
Over the last years he has focused on the generation of tools to perform functional genetic screens with special emphasis on loss-of-function cell based screens. To facilitate loss of function genetic screens he has developed large collections of shRNA knockdown vectors, targeting large numbers of both human and mouse genes. The development of these technologies has opened up the possibility to perform large scale mammalian somatic genetics.
To be able to peform large scale screens, he has set up the NKI Robotics and Screening Center (NSRC). This center facilitates the large scale and high throughput use of both genomic tools as well as compound collections. The NSRC is a resource center that provides the technology for medium to high throughput applications, provides support and expertise for automated cell and non-cell based assays and is used for the development, production and maintenance of large screening reagent collections. The NSRC has realized an automated high content screening platform with state-of-the-art image analysis software, database development and statistical analysis, integrated with bioinformatics to perform large scale complex phenotype cell based screens.
Co-workers
David Egan PhD Post-doc, NSRC
Pasi Halonen PhD Post-doc
Helena Aquilar PhD Post-doc
Johan Kuiken MSc Graduate student
Jeroen Nijwening MSc Graduate student
Cor Lieftink MSc Bioinformatician
Bram Gerritsen Bioinformatician
Wouter Nijkamp Technical staff
Ben Morris Technical staff