Characterization of the role of netrin-1 in the regulation of the Epithelial-to-Mesenchymal Transition during tumor progression.

Description du projet

Disséquer les marqueurs de cancer pour un traitement

La transition épithélium-mésenchyme (TEM) est un processus par lequel les cellules épithéliales sont transformées en cellules mésenchymateuses, ce qui leur confère la capacité de se détacher du tissu d’origine et de migrer vers d’autres sites. En dehors du développement normal, la TEM est active dans le cancer en stimulant la dissociation des cellules tumorales et des métastases, en plus de doter les cellules cancéreuses de propriétés de cellules souches et de résistance aux médicaments. Le projet NetriCan, financé par l’UE, va étudier comment une protéine extracellulaire, connue pour son rôle dans la migration cellulaire pendant le développement, régule la TEM dans les cellules cancéreuses. Les résultats du projet prouveront le potentiel thérapeutique d’une stratégie destinée à cibler cette protéine et faciliteront le développement de nouvelles approches thérapeutiques prometteuses pour les patients porteurs de tumeurs solides à un stade avancé.

Objectif

Recent data coming from both basic research and clinical trials converge toward the importance of the epithelial/mesenchymal status of a tumor to respond to conventional chemotherapies and immune-checkpoint inhibitors. These observations set the Epithelial-to-Mesenchymal Transition (EMT) program at the centre of cancer biology. Besides its multiple roles in development and during adulthood, EMT is activated during tumor progression not only to allow metastatic dissemination of cancer cells, which is responsible for the vast majority of patients’ death, but also to provide cells with stem-like properties and resistance mechanisms to survive chemotherapy. It is now widely accepted that future therapies will have to target and/or block the EMT process and allow conventional therapies to efficiently kill the differentiated, epithelial cells to treat patients with advanced solid tumors. NetriCan will analyse for the first time the implication of netrin-1 and its dependence receptor UNC5B in the regulation of EMT, either directly or via its cell death-related function. Moreover, the re-epithelialization effect of the anti-netrin-1 monoclonal antibody observed in tumors in vivo and in a preliminary cohort of patients shows that netrin-1/UNC5B may not only be involved in the direct regulation of maintenance of EMT but also serve as a survival mechanism for metastatic tumor cells. To achieve this, Netrican will first analyse how the upregulation of netrin-1 and UNC5B is regulated during EMT. It will then investigate the role of the netrin-1/UNC5B axis in the establishment and maintenance of the EMT program needed for cell dissemination and metastasis. Finally, this project will elucidate the therapeutic potential of the anti-netrin-1 strategy for both triggering primary tumor re-epithelialization and killing mesenchymal tumor cells. In summary, NetriCan will provide innovative findings to develop novel promising therapeutic approach for patients with advanced solid tumors.