Mutant p53 governs microenvironmental dynamics via exosomes and outer membrane vesicles

Background:

Mutations in TP53 are considered one of the most frequent genetic alterations in human cancer. Besides the abrogation of the wild-type (WT) p53-mediated tumor suppression, a distinct set of missense mutations was reported to endow mutant p53 proteins with novel activities termed gain-of-function (GOF). Even though mutations in TP53 are typically thought to arise in the tumor cells rather than in the stroma, the non-cell-autonomous effects of these mutants over the tumor microenvironment are poorly understood.

In the presented studies, focusing on colon cancer as well as on lung cancer microbiome, we investigated intercellular interactions mediated by exosomes and outer membrane vesicles (OMVs) in the context of cancers harboring mutant p53.

Results: In the colon, tumor cells harboring mutp53 were found to exert a non-cell-autonomous effect over macrophages. When exposed to tumor cells harboring mutp53, monocytes became polarized towards a distinguished subset of macrophages characterized by TAMs-related markers. The mutant p53 affected TAM were characterized as TNF-α^low/ IL-10^high, over expressing CD-206 and CD163, with decreased phagocytic ability and increased invasion and matrix degradation potency. Investigating the exosomal transfer from mutp53 tumor cells to macrophages, revealed a mutp53-specific miRs signature led by miR-1246 promoting the TAM phenotype and creating an invasive front together with tumor cells. MiR-1246 was also found to be the top mutp53-associated miR in a cohort of 57 human colorectal resected tumors.

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. We found a significant increase in tumor volume in animals inoculated with Acidovorax temperans as compared to Sham treated animals, and increased lung weight as a percent of total body weight. 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: Altogether, these findings are consistent with a microenvironmental role for specific “hot-spot” GOF p53 mutants tightening the interaction between the tumor cell and the immune compartment in colon cancer. In both colon and lung cancer, mutant p53 facilitates cellular interactions within the tumor microenvironmets mediated by vesicles.