Research project

Normal and pathological angiogenesis

Gilles PAGÈS, Research Director, DR1 Inserm

Our projects have focused on the ERK signaling pathway ; modulation of its activity, its role in tumor development (use of ERK1-/- mice) and its role in tumor angiogenesis (regulation of VEGF expression). We have highlighted regulators of VEGF expression that can serve as markers of tumor aggressiveness especially in the case of head and neck and breast cancers. We have established an original link between telomeric activity and the ERK signaling pathway. We are also interested in phenomena that could explain the varying efficiencies of Avastin/Bevacizumab (BVZ) depending on cancer origins. On models of breast and prostate cancers, the clinical efficiency of associations Taxol / BVZ could be explained by a direct effect on tumor cells expressing both VEGF and its receptor VEGF-R2. Clear cell renal cell carcinomas (RCC) express VEGF and pro-angiogenic factors of the family of ELR+CXCL cytokines. CXCL7 and CXCL8 (interleukin 8) are associated with increased mortality in patients. Monoclonal antibodies targeting CXCL7 and 8 are currently developed. In xenograft models of RCC tumors, BVZ accelerates tumor growth and induces the development of the lymphatic network that can explain the acceleration of the metastatic spread observed in patients.

Background of the team and self analysis

The group was created in 1999 when we moved from the Centre de Biochimie Parc Valrose to the Nice Cancer Centre, Centre Antoine Lacassagne (CAL). Our objectives were to decipher the links between activation of the ERK pathway and abnormal angiogenesis, two mains actors implicated in tumor development. Our localization at the CAL incited us to develop translational research aiming at reinforced the links with clinicians. My team was implicated in the discovery of new pertinent direct targets of ERK and on the molecular links between ERKs and regulation of VEGF expression at transcriptional and post transcriptional levels. Discussions with clinicians and our expertise on angiogenesis have oriented our thematic on the failure of anti-angiogenic therapies. The identification of the phosphorylation of the telomere binding factor TRF2 by ERK has established a new link between telomeric activity and activation of a major signaling pathway involved in tumor development.

Strengths : a strong interaction with clinicians and a solid expertise in the mechanisms of angiogenesis and on the ERK signaling pathway; the access to tumors samples in collaboration with different cancer centers (Nice, Lyon, Montpellier, Grenoble); the access to platforms (Animal house, imagery); the capacity to raise funds from national and international agencies, charities and private companies for manpower and consumables; the capacity to initiate clinical assays for an optimal transfer of the fundamental results to the clinic; valorization of the results of translational research through the filing of patent. Previous members of the team have obtained permanent positions at the University of Nice as assistant professors (Julie Milanini-Mongiat, Cercina Onesto), INSERM researcher (Sandrine Marchetti), clinic responsible (Laurence Legros) and researcher at the Pasteur Institute of Tunis (Khadija Essafi-Benkhadir). Olga Bermudez a PhD student who has defended her thesis in October 2009 realized currently a post doc with opportunity to develop her own team in Germany. The recent will of Dr Pascal Colosetti (engineer INSERM) to join my team.

Research teams