Michel Aguet

Biography

Dr. Michel Aguet, MD, held positions in academia and industry (Associate Professor at the Institute of Molecular Biology, University of Zürich; Head of Molecular Oncology, Genentech, So. San Francisco) before he was appointed director of the Swiss Institute for Experimental Cancer Research (ISREC) (1996-2009). In the context of the integration of ISREC into the Swiss Federal Institute of Technology (EPFL), he was appointed as Full Professor at the newly established School of Life Sciences in 2005. From 2001-2013 he directed the National Center of Competence in Research (NCCR) in Molecular Oncology, a national program launched by the Swiss National Science Foundation to encourage translational cancer research and for which ISREC was the leading house. Dr. Aguet has been a SAB member in the pharmaceutical industry, biotech industry and venture capital industry since 1997.

A large part of his scientific career was devoted to exploring the molecular biology of interferons (cloning of the interferon gamma receptor, generation of various interferon signaling mutants in the mouse) and, in collaboration with Prof. Charles Weissmann, to investigating the role of prion related protein PrP in mouse prion disease models. In recent years his research focused on characterizing the role of BCL9 proteins, which are part of the Wnt/beta-catenin transcriptional activation complex, in regulating stem cell traits in intestinal epithelium and colorectal cancer. His laboratory is now closed due to retirement.

Official source

https://people.epfl.ch/michel.aguet

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TBX3 acts as tissue-specific component of the Wnt/beta-catenin transcriptional complex

Michel Aguet, Andreas Eduard Moor

BCL9 and PYGO are beta-catenin cofactors that enhance the transcription of Wnt target genes. They have been proposed as therapeutic targets to diminish Wnt signaling output in intestinal malignancies. Here we find that, in colorectal cancer cells and in developing mouse forelimbs, BCL9 proteins sustain the action of beta-catenin in a largely PYGO-independent manner. Our genetic analyses implied that BCL9 necessitates other interaction partners in mediating its transcriptional output. We identified the transcription factor TBX3 as a candidate tissue-specific member of the beta-catenin transcriptional complex. In developing forelimbs, both TBX3 and BCL9 occupy a large number of Wnt-responsive regulatory elements, genome-wide. Moreover, mutations in Bcl9 affect the expression of TBX3 targets in vivo, and modulation of TBX3 abundance impacts on Wnt target genes transcription in a beta-catenin- and TCF/LEF-dependent manner. Finally, TBX3 overexpression exacerbates the metastatic potential of Wnt-dependent human colorectal cancer cells. Our work implicates TBX3 as context-dependent component of the Wnt/beta-catenin-dependent transcriptional complex.

ELIFE SCIENCES PUBLICATIONS LTD2020

Mutations in Bcl9 and Pygo genes cause congenital heart defects by tissue-specific perturbation of Wnt/beta-catenin signaling

Michel Aguet

Bcl9 and Pygopus (Pygo) are obligate Wnt/beta-catenin cofactors in Drosophila, yet their contribution to Wnt signaling during vertebrate development remains unresolved. Combining zebrafish and mouse genetics, we document a conserved, beta-catenin-associated function for BCL9 and Pygo proteins during vertebrate heart development. Disrupting the beta-catenin-BCL9-Pygo complex results in a broadly maintained canonical Wnt response yet perturbs heart development and proper expression of key cardiac regulators. Our work highlights BCL9 and Pygo as selective beta-catenin cofactors in a subset of canonical Wnt responses during vertebrate development. Moreover, our results implicate alterations in BCL9 and BCL9L in human congenital heart defects.

COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT2018

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Acute myelogenous leukemia (AML) is initiated and maintained by leukemia stem cells (LSC). LSCs are therapy-resistant, cause relapse, and represent a major obstacle for the cure of AML. Resistance to therapy is often mediated by aberrant tyrosine kinase (TK) activation. These TKs primarily activate downstream signaling via STAT3/STAT5. In this study, we analyzed the potential to therapeutically target aberrant TK signaling and to eliminate LSCs via the multi-TK inhibitor Debio 0617B. Debio 0617B has a unique profile targeting key kinases upstream of STAT3/STAT5 signaling such as JAK, SRC, ABL, and class III/V receptor TKs. We demonstrate that expression of phospho-STAT3 (pSTAT3) inAML blasts is an independent prognostic factor for overall survival. Furthermore, phospho-STAT5 (pSTAT5) signaling is increased in primary CD34(+) AML stem/progenitors. STAT3/STAT5 activation depends on tyrosine phosphorylation, mediated by several upstream TKs. Inhibition of single upstream TKs did not eliminate LSCs. In contrast, the multi-TK inhibitor Debio 0617B reduced maintenance and self-renewal of primary human AML CD34(+) stem/progenitor cells in vitro and in xenotransplantation experiments resulting in long-term elimination of human LSCs and leukemia. Therefore, inhibition of multiple TKs upstream of STAT3/5 may result in sustained therapeutic efficacy of targeted therapy in AML and prevent relapses. (C)2017 AACR.

Amer Assoc Cancer Research2017