Research Interest
Mouse Cancer Models
The aim is to utilize genetically engineered mouse models to define the (epi)genetic lesions involved in tumor initiation, progression, metastasis and tumor maintenance. These models are particularly suited to design and evaluate new intervention strategies.
Inducible mouse models
We have made a significant investment in developing new mouse models for a variety of tumors, using Cre/Lox mediated switching of tumor suppressor genes and oncogenes. Both transgenesis and somatic gene transfer are employed to express Cre recombinase and other genes or shRNAs in a regulatable fashion. The methodology enables us to switch multiple oncogenes and/or tumor suppressor genes within cells in vivo at a defined time and subsequently monitor the relevance of some of these genes for tumor maintenance. This permits the induction of highly specific tumors within a narrow time window, and allows us to correlate specific genetic defects with tumor characteristics. We have induced a range of tumors, including melanomas, lung tumors, squamous cell carcinomas, and mesotheliomas. The general picture that transpires from these studies is that the mouse models show closer resemblance to the human tumors when they share the same mutations. We apply sensitive in vivo imaging techniques to follow tumor growth and metastatic spread in real time in animals and monitor response to genetic and pharmacological interventions.
Retroviral insertional mutagenesis
Besides focusing on the function of specific oncogenes and tumor suppressor genes known to be involved in the tumors mentioned above, we utilize mouse models to identify new oncogenes and tumor suppressor genes. Slow transforming retroviruses, such as the Moloney murine leukemia virus (M-MuLV), induce tumors upon infection of a host after a relatively long latency period. These retroviruses can transform the infected host cells through the accidental insertion of their proviruses into the host genome in the vicinity of genes that can confer growth advantages to cells. This means that the proviral insertions found in tumors induced by retroviral insertional mutagenesis mark genes contributing to the tumorigenic process. Since cancer is a complex multistep process, the proviral insertions in one clone of tumor cells also represent oncogenic events that co-operate in tumorigenesis. Novel advances, such as the launch of the complete mouse genome, high-throughput isolation of proviral flanking sequences, and genetically modified animals have revolutionized proviral tagging into an elegant and efficient approach to identify signaling pathways that collaborate in cancer. This project is executed together with Maarten van Lohuizen in our department. We have identified over 600 putative oncogenes and tumor suppressor genes. This project is yielding an unexpected wealth of information on haploinsufficient tumor suppressor genes and specific cooperation of oncogenes. The human homologues of a subset of these genes map to human chromosomal regions that are frequently deleted or amplified in human tumors or found to carry mutations, thus validating and complement large-scale genomic analyses and sequencing efforts of cancer genomes.
Hunting down gene function
By focusing in more detail on some of the genes that were found in these retroviral tagging screens, such as the Pim and Frat families, we are trying to understand how proto-oncogenes confer their oncogenic potential. Therefore we study the normal function of these genes on the one hand by analyzing the phenotypic abnormalities in mice lacking one or more of these proto-oncogenes, and by characterizing the signaling pathways in which these genes act. The latter experiments are performed in cell culture systems using biochemical methods.
Key publications
Berns, A. (2002). "Senescence: a companion in chemotherapy?" Cancer Cell 1(4): 309-11.
Jonkers, J. and A. Berns (2002). "Conditional mouse models of sporadic cancer." Nature Rev Cancer 2(4): 251-65.
Marino, S., P. Krimpenfort, C. Leung, H. A. Van Der Korput, J. Trapman, I. Camenisch, A. Berns and S. Brandner (2002). "PTEN is essential for cell migration but not for fate determination and tumourigenesis in the cerebellum." Development 129(14): 3513-3522.
Vooijs, M., J. Jonkers, S. Lyons and A. Berns (2002). "Noninvasive imaging of spontaneous retinoblastoma pathway-dependent tumors in mice." Cancer Res 62(6): 1862-7.
Martins, C. P. and A. Berns (2002). "Loss of p27(Kip1) but not p21(Cip1) decreases survival and synergizes with MYC in murine lymphomagenesis." EMBO J 2: 3739-48.
Hwang, H. C., C. P. Martins, Y. Bronkhorst, E. Randel, A. Berns, M. Fero and B. E. Clurman (2002). "Identification of oncogenes collaborating with p27Kip1 loss by insertional mutagenesis and high-throughput insertion site analysis." Proc Natl Acad Sci U S A. 99: 11293-98.
Mikkers, H., Allen, J., Knipscheer, P., Romeyn, L., Hart, A., Vink, E., and Berns, A. (2002). High throughput retroviral tagging to identify components of specific signaling pathways. Nat. Genet. 32, 153-159.
Mikkers, H., and Berns, A. (2003) Retroviral insertional mutagenesis: Tagging cancer pathways. Adv. Cancer. Res. 88: 53-99
Marino, S., Hoogervoorst, D., Brandner, S., and Berns, A. (2003). Rb and p107 are required for normal cerebellar development and granule cell survival but not for Purkinje cell persistence. Development 130, 3359-3368.
Berns, A. (2003). Tumour suppressors: timing will tell. Nature 424, 140-141.
More publications by Anton Berns on PubMed
Biographic sketch
Anton Berns (1945) studied biochemistry at the University of Nijmegen and received his Masters degree in 1969 (cum laude) and his PhD in 1972 (supervisor Prof. H. Bloemendal) from that same University (cum laude). He did his postdoctoral training in the group of Rudolf Jaenisch at the Salk Institute in La Jolla, CA., where he studied the role of retroviruses in causing lymphomas in mice. In 1976 he returned to the University of Nijmegen where he became junior staff member. His group explored proviral insertional mutagenesis as a means to identify new oncogenes. In 1985 he was appointed as staff scientist at the Netherlands Cancer Institute and in 1986 he became head of the Division of Molecular Genetics of the Institute. Here his group did pioneering work to generate and utilize genetically modified mice as a tool to search for new cancer genes. Currently, his group focuses on the development and use of advanced mouse models for cancer. Themes of his current research are: i. Establishing of genotype – phenotype correlations of tumors using Cre-mediated switching of multiple oncogenes/tumor suppressor genes in a spatiotemporal controlled fashion. with emphasis on lung cancer models ii. Development of reliable readout system to permit noninvasive measurement of tumor-specific parameters as a way to evaluate new therapeutic intervention strategies, and iii. The use of high throughput proviral insertional mutagenesis to identify components in signaling pathways relevant for cancer (comparable to enhancer and suppressor screens in flies and worms). His group consists of approximately 15 post-docs and graduate students. From 1992-94 he also served as VP of Research of one of the leading gene therapy companies in the US. In 1999, he was appointed as Director of Research and Chairman of the Board of Directors of the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital. He continues to supervise his own research group besides the administrative tasks in and outside the institute.
Coworkers
Transgenic/KO research support
Dr Paul Krimpenfort
Dr Margriet Snoek
Huub van de Vugt
Fina van de Ahé
Rahmen bin Ali
Postdocs
Joaquim Calbo-Angrill
Kate Sutherland
Andor Kranenburg
Johan Jongsma
Jaap Kool
Anthony Uren
Renée van Amerongen
Hilda de Vries
Graduate Students
Andrej Alendar
Erwin van Montfort
Technicians
Ruben Gaasbeek
Natalie Proost
Jan-Paul Lambooij
Colin Pritchard
John Zevenhoven
Two independent investigators (research associates) with their own program and group share the lab:
Jaqueline Jacobs (telomere function)
Jan-Hermen Dannenberg (HDACs)
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