National Center of Competence in Research - NCCR Molecular Oncology

Prof. Michel Aguet

Prof. Michel Aguet received his MD in Zürich in 1974. He trained as a postdoctoral fellow with Dr. Ion Gresser in Villejuif, France, and moved back to the University of Zürich, where he became group leader at the Institute of Virology (Director Prof. Jean Lindenmann) and, in 1989, Associate Professor at the Institute of Molecular Biology (Director Prof. Charles Weissmann). In 1994, he moved to Genentech Inc., South San Francisco, to head the Molecular Biology Department. In 1996 he was appointed Director of ISREC, and in 2005 he became affiliated as a Full Professor at the EPFL School of Life Sciences

ISREC, School of Life Sciences Ecole Polytechnique Fédérale (EPFL)

Characterization of mouse Wnt pathway mutants / Identification of mediators of tumor cell invasion

Bcl9 and Pygopus (Pygo) were discovered in Drosophila as essential components of the Wnt canonical signaling pathway. Bcl9 binds to ß-Catenin and to Pygo and tethers Pygo to the ß-Catenin-Tcf activation complex (Kramps et al., Cell 109, 47-60, 2002). To elucidate the role of Bcl9 and Pygo during embryonic development and adult tissue homeostasis in the mouse, we generated loxP-flanked alleles of the four relevant genes (Bcl9, Bcl9l, Pygo1, Pygo2) and derived several conditionally mutant strains.

Role of Pygo 1/2 in mouse embryonic development

Ablating both Pygo orthologs in the mouse caused abnormalities including a striking defect in lens development, and a deficiency in cardiac neural crest cell expansion that resulted in lethal cardiac outflow tract and valve anomalies. Surprisingly, compound Pygo1/2 mutant embryos presented no anomalies in early Wnt mediated developmental processes. Accordingly, expression of known Wnt target genes was not significantly affected.

Role of Bcl9/Bcl9l in homeostasis and regeneration of adult gastrointestinal epithelium

In the gastrointestinal epithelium, locally confined Wnt signals regulate and compartmentalize cell proliferation and differentiation along the crypt villus axis. Surprisingly, ablation of Bcl9 and Bcl9l in the adult gastrointestinal epithelium did not result in any detectable anomaly and had no effect on cell proliferation and lineage determination. However, mutant mice proved highly susceptible to the irritant dextrane sulfate sodium (DSS) and displayed epithelial lesions that were markedly more extended as compared to wild-type mice (see Figure 1). Transcriptional profiles of epithelium micro-dissected at different time points of DSS treatment are currently compared. Preliminary results indicate that stress responses to DSS are indistinguishable, and that the anomaly is rather due to impaired epithelial regeneration during wound-healing. The comparison of genes differentially expressed during the regenerative phase is expected to provide hints regarding affected genes, and to clarify to what extend the anomaly can be attributed to altered Wnt-signaling.

Role of Bcl9 and Pygo proteins in tumor development

Constitutive activation of Wnt/ß-catenin signaling is an initiating event in the development of colorectal carcinomas in humans. To assess the role of Pygo and Bcl9 proteins in colorectal tumorigenesis, colon tumors were induced in mice through exposure to the mutagen N,N'-dimethylhydrazine (DMH) and subsequent challenge with DSS. Unexpectedly, wild-type and Bcl9/Bcl9l or Pygo1/2 mutants developed tumors to the same extent and tumors had comparable morphology. Wnt signaling, as assessed by expression level of the Wnt target gene Axin2, was activated to a similar extent in wild-type and mutant tumors.

While it cannot be ruled out that Pygo1/2 and Bcl9/Bcl9l may be required for discrete spatial and/or temporal activation of Wnt-regulated genes during embryonic development and adult tissue regeneration, their role as obligatory transcriptional co-activators of Wnt target genes in Drosophila does not appear to be conserved in the mouse.

Exploring the microenvironment of human colon cancer

There is increasing evidence that tumor cells actively recruit stromal cells, such as inflammatory cells, vascular cells, and fibroblasts, into the tumor. The resulting microenvironment seems to play an important role in tumor progression. Dissecting this intercellular cross-talk and the underlying molecular pathways might provide new rationales for inhibiting tumor progression through targeting the tumor microenvironment in addition to the tumor cell.

The objectives of this project are to identify genes that are differentially expressed at the invasive tumor front and to use genetically engineered and/or xenograft mouse models to explore the functional relevance of candidate genes for promoting tumor growth, invasion and dissemination. Using laser capture micro-dissection of colon carcinoma tissue from freshly operated patients, we have established a database of genes differentially expressed in tumor versus normal epithelium, and in quiescent versus reactive tumor stroma. A mouse xenograft platform has been established to modulate expression of candidate genes in established tumors using lentivirus-based conditional shRNA or cDNA expression (Wiznerowicz and Trono, J. Virol. 77, 8957-8961, 2003) and to monitor tumor growth. Proof of concept has been obtained with colon carcinoma cell lines in which genes known to affect tumor proliferation have been attenuated (ß-catenin; HectH9, a regulator of Myc-mediated target gene expression). These models are currently adapted to focus more on monitoring tumor invasion and metastatic dissemination.

Early diagnosis is likely to improve the outcome and prognosis of most solid tumors. While proteomic profiling for tumor marker discovery has hold particular promise, the use of biomarker screening has so far been limited to prostate cancer. A side project has emerged from our gene discovery effort at the invasive tumor front that aims at exploiting the activity of some genes as a means for detecting predictable degradation products as early potentially diagnostic markers of invasiveness. Our current work focuses increasingly on establishing proof for this concept.

List of publications

van Bezooijen, R. L., Deruiter, M. C., Vilain, N., Monteiro, R. M., Visser, A., van der Wee-Pals, L., van Munsteren, C. J., Hogendoorn, P. C., Aguet, M., Mummery, C. L., Papapoulos, S. E., Ten Dijke, P., and Lowik, C. W. SOST expression is restricted to the great arteries during embryonic and neonatal cardiovascular development. Dev Dyn 236, 606-61 (2007)

Wilson, A., Ardiet, D. L., Saner, C., Vilain, N., Beermann, F., Aguet, M., Macdonald, H. R., and Zilian, O. Normal hemopoiesis and lymphopoiesis in the combined absence of numb and numblike. J Immunol 178, 6746-6751 (2007)

Wang, X. D., Leow, C. C., Zha, J., Tang, Z., Modrusan, Z., Radtke, F., Aguet, M., de Sauvage, F. J., and Gao, W. Q.. Notch signaling is required for normal prostatic epithelial cell proliferation and differentiation. Dev Biol 290, 66-80 (2006)

Sperisen, P., Schmid, C. D., Bucher, P., and Zilian, O. Stealth proteins: in silico identification of a novel protein family rendering bacterial pathogens invisible to host immunedefense. PLoS Comput Biol 1, e63 (2005)

Klein, AL, Zilian, O, Suter, U, and Taylor, V. Murine numb regulates granule cell maturation in the cerebellum. Dev Biol 266, 161-177 (2004)

Genoud, S., Lappe-Siefke, C., Goebbels, S., Radtke, F., Aguet, M., Scherer, S. S., Suter, U., Nave, K. A., and Mantei, N. Notch1 control of oligodendrocyte differentiation in the spinal cord. J Cell Biol 158, 709-718 (2002)

Lütolf, S., Radtke, F., Aguet, M., Suter, U., and Taylor, V. Notch1 is required for neuronal and glial differentiation in the cerebellum. Development 129, 373-385 (2002)

Zilian, O., Saner, C., Hagedorn, L., Lee, H.-Y., Säuberli, E., Suter, U., Sommer, L., and Aguet M. Multiple roles of mouse Numb in tuning developmental cell fates. Curr. Biol. 11, 494-501 (2001)

Rangarajan, A., Talora, C., Okuyama, R., Nicolas, M., Mammucari, C., Oh, H., Aster, J. C., Krishna, S., Metzger, D., Chambon, P., Miele, L., Aguet, M., Radtke, F., and Dotto, G. P. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J 20, 3427-3436 (2001)

Radtke, F., Ferrero, I., Wilson, A., Lees, R., Aguet, M., and MacDonald, H.R. Notch1 deficiency dissociates the intrathymic development of dendritic cells and T cells. J. Exp. Med. 191(7), 1085-1094 (2000)

Gerber, H.P., Hillan, K.J., Ryan, A.M., Kowalski, J., Keller, G.A., Rangell, L., Wright, B.D., Radtke, F., Aguet, M., and Ferrara, N. VEGF is required for growth and survival in neonatal mice. Development 126, 1149-1159 (1999)

Radtke, F., Wilson, A., Stark, G., Bauer, M., van Meerwijk, J., MacDonald, H.R., and Aguet, M. Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immun. 10, 547-558 (1999)

Kaplan, D.H., Shankaran, V., Dighe, A.S., Stockert, E., Aguet, M., Old, L.J., and Schreiber, R.D. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc. Natl. Acad. Sci. U.S.A. 95, 7556-7561 (1998)

Spencer, S.D., Di Marco, F., Hooley, J., Pitts-Meek, S., Bauer, M., Ryan, A.M., Sordat, B., Gibbs, V.C., and Aguet, M. The orphan receptor CRF2-4 is an essential subunit of the interleukin 10 receptor. J. Exp. Med. 187, 571-578 (1998)

Bach, E. A., Aguet, M., and Schreiber, R. D. The IFN gamma receptor: a paradigm for cytokine receptor signaling. Annu Rev Immunol 15, 563-591 (1997)

Bachmann, M. F., Kalinke, U., Althage, A., Freer, G., Burkhart, C., Roost, H., Aguet, M., Hengartner, H., and Zinkernagel, R. M. The role of antibody concentration and avidity in antiviral protection. Science 276, 2024-2027 (1997)

Merlin, G., van der Leede, B. J., McKune, K., Knezevic, N., Bannwarth, W., Romquin, N., Viegas-Pequignot, E., Kiefer, H., Aguet, M., and Dembic, Z. The gene for the ligand binding chain of the human interferon gamma receptor. Immunogenetics 45, 413-421 (1997)

Wang, B., Andre, I., Gonzalez, A., Katz, J. D., Aguet, M., Benoist, C., and Mathis, D. Interferon-gamma impacts at multiple points during the progression of autoimmune diabetes. Proc Natl Acad Sci U S A 94, 13844-13849 (1997)