Functional roles of GOF TP53 mutations in metastasis and immunosuppression of head and neck cancers

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Project Summary/Abstract TP53 is the most common somatically mutated gene among all cancers as it is altered in up to 85% of head and neck squamous cell carcinomas (HNSCC). Although TP53 mutations often lead to a loss of wild-type p53 (wtp53) function, many TP53 mutations confer mutant p53 (mutp53) gain-of-function (GOF), promoting cancer cell genomic instability, proliferation, invasion, metastasis, and cancer inflammation. However, the mechanisms involved in mutp53 GOF activity remain largely elusive, which is a major obstacle to fully understanding and targeting mutp53 to prevent tumorigenesis and tumor progression of HNSCC. Our long-term goal is to understand the role of TP53 mutations in promoting tumorigenesis and tumor progression of HNSCC and to use this knowledge to develop effective targeted therapies for HNSCC. The objective of this proposed research, which is the next step in pursuit of that goal, is to identify the specific role of GOF mutp53 in the promotion of chromosomal instability (CIN), which leads to tumor metastasis and immunosuppression, and to further exploit this to design novel treatment strategies for HNSCC. Our central hypothesis is that by targeting MCM5, a component of the replication licensing factor minichromosome maintenance 2-7 complex (MCM2-7), GOF mutp53 predisposes cells to CIN that leads to a STING-dependent cytosolic DNA response involving downstream activation of non-canonical nuclear factor kappa light chain enhancer of activated B cell (NF-κB) signaling, which, in turn, promotes tumor cell invasion, metastasis, and immunosuppression; therefore, targeting mutp53-mediated signaling can be used as a therapeutic strategy for HNSCC in patients with GOF TP53 mutations. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine the functional roles of GOF mutp53-MCM5-cGAS/STING-non-canonical NF-κB signaling in the promotion of tumor invasion and metastasis in HNSCC cells; 2) Determine the functional roles of GOF mutp53- MCM5-cGAS/STING-non-canonical NF-κB signaling in the promotion of immunosuppression in HNSCC; 3) Identify novel therapeutic strategies for HNSCC with GOF p53 mutations. The research proposed in this application is highly innovative, given that the proposed mechanisms for studying GOF mutant p53 have never been reported before. Our hypothesis is based on our strong preliminary results from a proteomic screen of the mutp53 interactome, which uncovered a physical interaction between GOF mutp53 proteins and MCM5. We expect that the proposed work will identify intrinsic mechanisms of mutp53-mediated GOF in the promotion of genomic instability, metastasis, and immunosuppression that contribute to tumor development and tumor progression of HNSCC. Given the high incidence of p53 mutations in HNSCC, the proposed research is expected to have a significant impact on the public health burden of this deadly disease, and will help us develop novel therapeutic strategies to treat HNSCC patients with TP53 mutations.