Prof. Dr. Gerhard Christofori

Born 1957 Tel: +41 61 267 3562 Email: gerhard.christofori@unibas.ch Studied Biology at the University of Heidelberg. Obtained a PhD in the laboratory of Walter Keller at the German Cancer Research Center and at the Biocenter of the University Basel on the biochemistry of 3' processing and polyadenylation of eukaryotic messenger RNA. In 1989, joined the laboratory of Douglas Hanahan at the UCSF, USA, as a postdoctoral fellow to study the molecular mechanisms of multistage tumor development. In 1994, became a junior group leader at the Institute of Molecular Pathology (IMP) in Vienna, Austria. Since Sept. 2001, Professor and Chair of Biochemistry at the Institute of Biochemistry and Genetics, Department of Biomedicine, University of Basel, Switzerland. Since January 2007, Vice-Dean of Research at the Medical Faculty of the University of Basel. Past Research The emergence of high-throughput technologies has changed the way biological problems are approached. Sophisticated computational methods applied to large-scale datasets of sequences and expression profiles allow one to now simultaneously study the response of many genes and biological pathway to developmental and environmental stimuli. My first contribution in computational biology was an analysis of the spectrum of mutations that took place during somatic hypermutation of immunoglobulin genes and during evolution of pseudogenes, which lead to the hypothesis of a two-tiered mechanism underlying somatic hypermutation. Experimental data in support of this model has recently started to emerge. I have then participated in a number of studies of large-scale sequence data generated at the Riken Institute. My contributions were to show that alternative splicing is very frequent in mouse, that alternative exons differ from constitutive ones in a number of regulatory sequence motifs, and that alternative transcription start sites can be coupled with the changes in downstream splicing. Since I have established my group at the Biozentrum in Basel, we have focused to a large extent on small regulatory RNAs. We have contributed to the discovery of virus-encoded miRNAs, of many mammalian miRNAs, and of the principles of miRNA-target recognition. Currently, we are investigating the regulation of mRNA metabolism by small RNAs and RNA-binding proteins.   Current projects Our current research interests are aimed at combating cancer by unraveling the molecular mechanisms underlying malignant tumor progression and are motivated mainly by two notions: (1) 90% of cancer patients die of metastases and (2) metastatic dissemination of tumor cells is not only induced by genotypic or phenotypic changes within the tumor cells themselves but also by the tumor microenvironment. To investigate the molecular mechanisms that govern tumor cell migration, invasion and metastatic dissemination we are employing a combination of biochemical and cell biological approaches, transgenic mouse models of carcinogenesis, patient biopsies, and gene profiling and bioinformatics technology. Currently, we are addressing the following questions: 1. What are the molecular signaling pathways that are elicited by changes in cell-cell and cell-matrix adhesion, and how do they affect cell migration, invasion, and metastatic dissemination? 2. What is the contribution of the tumor microenvironment to tumor progression? Moreover, what are the molecular cues for organ-specific homing of metastatic tumor cells? 3. What is the contribution of blood vessel angiogenesis and lymph angiogenesis to tumor metastasis?   Research within the Node   Our research group currently employs refined transgenic mouse models of carcinogenesis to unravel the molecular mechanisms underlying tumor progression and metastasis formation. A major focus in our laboratory is based on the observation that epithelial-mesenchymal transition (EMT) that is underlying the malignant conversion of tumor cells is not only induced by genetic but also by epigenetic changes within the tumor cells themselves. To elucidate the nature of these genetic and epigenetic events and to modulate their function during tumor progression, we have established a number of cellular systems and transgenic mouse models of breast carcinogenesis in which EMT can be modulated. Recent results indicate that EMT is a multistep process and, currently, our laboratory is performing experiments to delineate the regulation of these multiple stages of EMT at the level of transcriptional control, including the epigenetic regulation of gene expression during EMT, tumor progression and metastasis. We envision that the knowledge about the epigenetic imprint of malignant cancer cells is a pre-requisite to devise approaches towards their normalization, i.e. the design of innovative anti-metastatic cancer therapy.

Relevant publications:

Perl, A.-K., Wilgenbus, P., Dahl, U., Semb, H., and Christofori, G. (1998) A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 392, 190-193. Perl, A.K., Dahl, U., Wilgenbus, P., Cremer, H., Semb, H., and Christofori, G. (1999) Reduced expression of neural cell adhesion molecule (N-CAM) induces metastatic dissemination of pancreatic b tumor cells. Nature Med. 5, 286-291 Cavallaro, U., Niedermeyer, J., Fuxa, M., and Christofori, G. (2001) N-CAM modulates integrin-mediated cell adhesion by activating FGF receptor signalling. Nature Cell Biol. 3, 650-657. Wicki, A., Lehembre, F., Wick, N., Hantusch, B., Kerjaschki D., and Christofori, G. (2006) Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the cytoskeleton. Cancer Cell 9, 261-272. Grotegut, S., von Schweinitz, D., Christofori, G., and Lehembre, F. (2006) Hepatocyte growth factor/scatter factor (HGF/SF) induces cell scattering through MAPK/Egr-1-mediated upregulation of Snail. EMBO J. 25, 3534-3545. Lehembre, F., Yilmaz, M., Wicki, A., Schomber, T., Strittmatter, K., Ziegler, D., Kren, A., Went, P., Derksen, P., Berns, A., Jonkers, J., and Christofori, G. (2008) NCAM-induced focal adhesion assembly: a functional switch upon loss of E-cadherin. EMBO J. 27, 2603-2615.