Senescence and its secretome: friend or foe of pancreatic cancers
Description: Pancreatic ductal adenocarcinomas (PDA) are deadly cancers for which the development of innovative therapeutics is required. Oncogenic KRAS mutation is the major driver of PDA. Interestingly, KRAS activation also results in an oncogenic-induced-senescence (OIS) in normal cells. While KRAS-OIS prevents cell proliferation and should block tumor initiation and progression, it drives the production of a complex secretome termed SASP (senescence associated secreted phenotype) which pro- or anti-tumoral role in PDA remain actively debated. Our project aims at understanding and dissecting the exact role of KRAS-driven senescence as well as identifying the composition and the function of the SASP-secretome of KRAS-senescent cells in pancreatic cancer. To this end, we will use primary cultures of pancreatic acinar cells exposed to KRAS activation to define the mechanisms driven by senescence in those cells and identify the diversity of their SASP-signature(s) through transcriptomics, proteomic and single-cell RNAseq amalysis. Engineered mouse-models expressing Kras will be used to address the consequences of modulating identified SASP candidates on the formation PanIN and their progression to PDA. Finally, results will be validated and further studied using human samples and histopathological analyses from the large PACAOmic cohort. This innovative project is based on complementary expertise of 2 teams and a large amount of preliminary results. It should lead to a better understanding of the role of OIS and of its secretome (SASP) in controlling the transformation of pancreatic acinar cells that drive the formation of pancreatic cancers. It should lead to the identification of means to control the initiation and the progression of PDA and might therefore favor the clinical progress for their therapeutics.
Funder: Institut National Du Cancer
Amount: €497,100
Funding type: grant
Funder scheme: Projets libres de Recherche « Biologie et Sciences du Cancer »
Investigator: Juan IOVANNA
Institution: INSERM U1068
Funded outputs count: 1
Funder award ID: INCa-14908
OpenAlex ID: G6173595841