SCOPE: Phospholipase D Promotes Oral Cancer Tumorigenic Functions by Regulating Cellular Bioenergetics

HPV-negative squamous cell carcinomas of the oral cavity and oropharynx (OPSCC) frequently present aslocally advanced disease with more than half of all patients experiencing disease relapse and a 5-year survival rate of around 25% for these patients. Standard-of-care therapies include surgery, radiation, and conventional chemotherapies which often lead to severe morbidity and disfigurements that diminish patient quality of life. Recent studies have determined that mitochondrial capacity and metabolic adaptations may be the key to chemotherapy resistance and tumor recurrence. Thus, identifying druggable targets that regulate mitochondrial functions and bioenergetics may be critical for improving treatment outcomes. Here we have identified phospholipase D (PLD) as a novel regulator of OPSCC mitochondrial function. PLD expression is highly upregulated in OPSCC tumors and drives OPSCC tumorigenic functions, metabolic gene expression, and mitochondrial capacity. We hypothesize that PLD drives OPSCC tumorigenesis by regulating mitochondrial functions which may targetable as a monotherapy or in combination with conventional chemotherapies. This proposal seeks to determine the in vitro and in vivo mechanisms of bioenergetic regulation by PLD and whether PLD promotes chemoresistance. We will first measure activities of mitochondrial proteins in vitro following PLD inhibition or knockout in OPSCC cells. Next, we will perform metabolomic analyses in model systems to map metabolic pathways regulated by PLD. Finally, we will determine if chemotherapy resistant cell lines are sensitive to PLD inhibition and if PLD inhibitors synergize with chemotherapies to reduce OPSCC proliferation. These studies will facilitate development of novel therapeutic interventions for these under-investigated and aggressive cancers.