Functionalizing recurrent FAT1 mutations and deletions in oral cancer Oral squamous cell carcinoma (OSCC) is a lethal disease with survival rates that have stalled, despite an expanding and increasingly comprehensive catalog of the genetic alterations occurring in these tumors. In the post-genomic era, treatment advances in OSCC require systematic research that closes a gap by linking cancer genes to cancer processes, and cancer processes to acquired vulnerabilities. Recently, recurrent mutations and deletions affecting the gene FAT1 have been identified in head and neck squamous cell carcinoma (HNSCC). After TP53, FAT1 is the second-most prevalent gene mutation in HNSCC. The precise mechanism by which FAT1 loss-of-function operates in OSCC, its cellular and clinical consequences, and any potential vulnerabilities it engenders, have not been explored. Our long-term goal is to translate the dividend of cancer genome data into new avenues of precision therapy, by functionally dissecting molecular alterations in oral and head and neck cancer. The candidate's long term goal is to develop a research career as a clinician-scientist who is able to independently perform genomic discovery, advanced bioinformatic analyses, and functional molecular investigation of genetic processes that drive OSCC. As a first step toward these long-term goals, the objective of this proposal is to characterize, in detail, the function o FAT1 in the 30% of oral cancers harboring inactivation of this gene. In 2013, the candidate first reported the presence of recurrent FAT1 mutations in multiple cancer types, including OSCC, and showed that FAT1 functions as a tumor suppressor gene that is the target of widespread deletion of 4q35.2 in human cancer. More recently, pan-cancer analyses have identified FAT1 as the 7th most frequently mutated gene across 21 types of cancer. Based upon our preliminary data, we hypothesize that FAT1-inactivated OSCC is a distinct subtype of malignancy, driven by upregulated Wnt signaling and altered squamous lineage differentiation, and displaying unique clinical behavior. The rationale for this research is that understanding FAT1-inactivated OSCC will inform precise clinical trial design, and immediately direct pre- clinical research with targeed agents. We have the following 3 specific aims. In Aim 1, we will dissect the consequences of FAT1 inactivation in OSCC, focusing on cellular behavior, altered cancer signaling pathways, and therapeutic vulnerabilities. In Aim 2, we will examine the impact of inactivation concurrently targeting FAT1 and other squamous differentiation genes, on OSCC development and aggressiveness. In Aim 3, we will determine the prognostic ramifications of FAT1 inactivation in OSCC, in the context of other clinical covariates. These studies will be carried out using in vitroand in vivo models of OSCC, and primary patient samples. This innovative work will demonstrate the therapeutic potential of targeting heretofore unconsidered biologic processes in OSCC. During the training period, the candidate will gain proficiency in advanced bioinformatics techniques and mouse modeling through substantive hands-on experience and formal training. The research and training plan will be completed by the candidate under the close guidance of primary mentor Dr. Timothy Chan at Memorial Sloan-Kettering Cancer Center (MSKCC), who is an accomplished cancer genomics researcher. In addition, expert guidance will be provided by a team of co-mentors, who include Dr. James Fagin at MSKCC, an expert on transgenic mouse models of cancer and signal transduction networks; Dr. Andrew Dannenberg at Weill Cornell Medical College, an expert on animal models of carcinogen-induced tumors; and Dr. Brian Schmidt at New York University, an expert on oral cancer biomarkers. Together, the seasoned mentoring team also provides input on scientific development through critique of experimental design and data analysis, and strategic input on publications, presentations, and grant writing. The candidate has the benefit of a rich research environment at a world-leading cancer research center and the committed support of clinical chairs, research department leadership, and the institution. Altogether, completion of this proposal will position the candidate for an independent career in OSCC and HNSCC genomics and cancer biology.