Remodeling of Dietary Fat into Protumorigenic Signaling Lipids in Cancer (PQ1)

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DESCRIPTION (provided by applicant): Obesity has been linked to enhanced cancer mortality across almost all cancer types. Recent studies have provided mechanistic insights into how obesity can contribute to tumorigenesis through enhanced insulin signaling or low-grade inflammation. We have recently also uncovered a potential link between obesity and cancer malignancy in which aggressive cancer cells exhibit heightened levels of free fatty acids which in-turn are transformed into oncogenic signaling lipids, such as lysophosphatidic acid and prostaglandins, which in turn drive aggressive features in cancer. We previously showed that an enzyme, monoacylglycerol lipase (MAGL), upregulated across multiple human aggressive cancer cells and primary tumors, drives this lipolytic release of free fatty acids and that blockin MAGL suppressed fatty acid release and subsequent formation of LPA and prostaglandins leading to suppressed cancer cell aggressiveness and tumor growth. Quite provocatively, however, these defects in cancer pathogenicity were rescued by addition of exogenous fatty acids in vitro or high-fat diet in vivo, giving rise to the intriguing hypothesis that the role of AGL in supplying cancer cells with FFAs can be supplanted by exogenous sources of fat. This remodeling of exogenous fatty acids into either structural or signaling lipid components for the cancer cell requires both fatty acid transport into the cells and enzymatic processes that would incorporate fatty acids units into complex lipids, thereby giving rise to the possibility of targetng these FFA-transport or metabolic pathways for therapeutic intervention to thwart obesity-related effects on cancer. This proposal will map metabolic pathways that remodel dietary fat into protumorigenic signaling lipids to drive cancer malignancy using advanced metabolomic approaches.