Investigating the Cellular and Molecular Correlates of Malignancy in Li-Fraumeni Syndrome

Li-Fraumeni Syndrome is a cancer predisposition syndrome associated with germline TP53 mutations. LFS patients are faced with a significant lifetime cancer risk, which necessitates the identification of cancer prevention strategies. Chemical mTORC1 inhibitors delay cancer onset and extend lifespan in LFS mice, suggesting that mTORC1 favors tumorigenesis in LFS. We show that LFS patient-derived fibroblasts harboring the R248Q p53 mutation exert a pro-tumorigenic influence when co-injected with cancer cells into mice. This influence was negated by rapamycin, suggesting that this pro-tumorigenic phenotype is mTORC1-dependent. To that end, mutant fibroblasts exhibit increased mTORC1 activity and vulnerability to mTORC1 inhibition compared to p53 wildtype fibroblasts. We further show that the secretome of mutant versus wildtype fibroblasts differs, and secretion of certain pro-tumorigenic cytokines is mTORC1-dependent. Our findings suggest that mutant-p53 driven mTORC1 activation promotes a functional dependency on mTORC1 signaling, revealing a vulnerability that may exploited to limit the oncogenicity of mutant p53.M.Sc