CRCINA - INSERM UMR1232
Department "Oncogenesis and new concepts in oncology (ONCO)"
Team 12 "Targeted Therapies in Colorectal Cancer"
In response to chemotherapy, mammalian cells undergo either apoptosis or senescence, a long term cell cycle exit where cancer cells remain viable but proliferation is definitely arrested. Initially characterized in primary cells, animal models and human biopsies have demonstrated that senescence limits tumor progression and is necessary for chemotherapy response. It is however unclear if chemotherapy-induced senescence (CIS) is always irreversible and if some cells can preserve their proliferative potential. For instance, deleting PTEN after senescence induction restores proliferation of BRAF-arrested melanocytes. During the last years, we have described that the STAT3 pathway plays an important role in CIS resistance during the acute response. We recently detected subpopulations that adapted to CIS, resumed proliferation and that were not intrinsically resistant or enriched with current markers of cancer intiating cells. This population is more transformed and invasive, it induced tumor formation in mice, grew in low adhesion, resisted anoikis and favored angiogenesis. Importantly, CIS escape generates an heterogeneous population, composed of dividing cells (30%) and senescent cells (70%). This adaptive mechanism relying on different sub-clones has already been described in bacteria where persister bacteria resist antibiotic treatment and reconstitute a full population. We used quantitative proteomic analysis on tumor samples to identify secreted proteins involved in the generation of this survival niche. We described and patented the first proteomic signatures of the successive stages of colorectal cancer and of triple negative breast cancers. We focused this approach on the tumor secretome and identified specific markers of different stages that can be detected in the blood. We are currently determining if these soluble proteins are involved in treatment failure and CIS escape. This will allow the characterization of this intratumoral surviving niche that allows CIS resistance and the generation of more aggressive cells.
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