Mutant p53 governs microenvironmental dynamics via exosomes and outer membrane vesicles

Ishai Luz ¹ Ioannis Pateras ² Vassilis Gorgoulis ³ Curtis Harris ⁴ Tomer Cooks ¹

¹Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel
²Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Greece
³Histology and Embryology,, School of Medicine, National and Kapodistrian University of Athens, Greece
⁴Laboratory of Human Carcinogenesis, National Institutes of Health, USA

Mutations in TP53 are considered one of the most frequent genetic alterations in human cancer. 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.

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. 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.

Separately, 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.

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 and lung cancer.