Pancreatic cancer (PDAC) is one of the rare cancers with still increasing incidence and mortality over the time and should become the second cause of death by cancer by 2030. It is so aggressive that it can be considered as a model to study acquisition of resistance to treatments by tumoral cells. Nowadays, mainly two treatments are employed, the classical one with Gemcitabine and the later one which is a protocol associating the successive use of three different chemicals, 5FU, Irinotecan and Oxaliplatin. But the relative efficacy of these treatments remains limited and most patients rapidly acquire resistance to any antitumoral drug. Our goal is to identify new universal resistant mechanisms that explain this particularly extreme phenotype of PDAC cells.
These mechanisms are dependent on the activation of stress response pathways which rely on the post-translational modifications (PTMs) of involve proteins. PTMs mediated by the ubiquitin family of proteins (including ubiquitin itself and number of ubiquitin-likes) are now well-known to regulate most biological processes of a normal cell and the number of examples of alterations of this system associated with pathologies, like cancers, is constantly increasing.
We have used a PDAC cell line named MiaPaCa-2 and advance proteomics in order to identify alterations of ubiquitination, neddylation, and sumoylation (the most common type of PTMs by ubiquitin family) associated with chemotherapy induced stress responses as well as alterations associated with the acquired resistant phenotype to diverse anticancer chemicals. We have been able to identify number of important alterations of PTMs, could validate some of them, and demonstrate their implication in the survival of PDAC cells when subjected to chemotherapy.
Ce séminaire sera présenté par Philippe SOUBEYRAN du Centre de Recherche en Cancérologie de Marseille.
** Entrée libre **