Grant: Travel Awards - Institute Community Support

Cellular senescence is a powerful intrinsic anti-cancer mechanism characterized by a stable cell proliferation arrest. As a result, several pharmaceutical companies and laboratories are working on anti-cancer therapies following this idea. Therefore, elucidation of the processes regulating the onset and maintenance of senescence will help to identify pro-senescence therapies for cancer. In the Ferbeyre laboratory, we aim to identify key factors specifically regulated by the RAS/MAPK pathway, that mediate the commitment of cells towards cellular senescence. Importantly, it is well known that 30% of all human cancers have an activating mutation in the RAS oncogene, which leads to an increased proliferation rate. However, it is also known that, through an unknown mechanism, a sustained hyper-activation of this same pathway leads to an antagonistic phenotype, which is, cellular senescence. This cellular fate characterizes benign lesions, and progression into a malignant tumor is associated to the bypass of this intrinsic anti-cancer program. Recent results obtained in our lab allowed us to define a time window of activation of the RAS/MAPK pathway leading to a "pre-senescence" state where cells are negative for classic senescence markers at this moment, but committed towards cellular senescence within seven days. Our working hypothesis is that hyperactivation of RAS/MAPK pathway leads to important transcriptional changes occurring during this precise short time window, and that it is these changes that are crucial to compromise cells towards cellular senescence. We are confident that our research will not only lead to identification of novel senescence biomarkers, but also to identification of senescence drivers. This will ultimately allow the design of novel therapeutic strategies aiming to promote and maintain the senescent state and inhibit progression of RAS-mutated cancers, in order to eliminate these senescent cells afterwards via the use of senolytic drugs.