Mutant p53 governs tumor microenvironment dynamics via extracellular vesicles and bacterial outer membrane vesicles

Pancreatic Ductal Adeno carcinoma (PDAC) has a poor survival rate. In PDAC, the activation of normal (quiescent) fibroblasts leads to the secretion of tumor-promoting factors and to active remodeling of the cancer associated fibroblasts (CAF) generated ECM. We hypothesize that GOF p53 signaling promote ECM production that favors PDAC cell survival by the production of unique extracellular vesicles (EVs). We based our method on a well-established 3D system for ECM deposition. EVs isolation was done according to the MISEV 2018 guidelines. Our findings suggest that mutp53 GOF EVs taken up by CAFs promote changes of fiber deposition, orientation, and ECM thickness.

Separately, in two lung cancer cohorts, we identified a signature of microbiome members associated with p53 mutations. Acidovorax Temperans, a Gram negative bacterium, was found to be abundant in tumors of patients with mutant p53. There is a significant increase in tumorigenesis in animals inoculated with Acidovorax temperans as compared to Sham treated animals. These preliminary data indicate that Acidovorax temperans contributes to lung tumorigenesis in the presence of activated K-Ras and mutant p53. OMVs shed by Acidovorax temperans promoted inflammatory signaling in lung carcinoma cells and elevated CD47 expression on tumor cells and SIRPα levels on macrophages.

Conclusions: We show a microenvironmental role for specific “hot-spot” GOF p53 mutants tightening the interaction between the tumor cell and the immune compartment. Mutant p53 facilitates cellular interactions within the tumor microenvironments mediated by vesicles.