Monoacylglycerol Lipase Regulates a Fatty Acid Network that Promotes Cancer Pathogenesis

SummaryTumor cells display progressive changes in metabolism that correlate with malignancy, including development of a lipogenic phenotype. How stored fats are liberated and remodeled to support cancer pathogenesis, however, remains unknown. Here, we show that the enzyme monoacylglycerol lipase (MAGL) is highly expressed in aggressive human cancer cells and primary tumors, where it regulates a fatty acid network enriched in oncogenic signaling lipids that promotes migration, invasion, survival, and in vivo tumor growth. Overexpression of MAGL in nonaggressive cancer cells recapitulates this fatty acid network and increases their pathogenicity—phenotypes that are reversed by an MAGL inhibitor. Impairments in MAGL-dependent tumor growth are rescued by a high-fat diet, indicating that exogenous sources of fatty acids can contribute to malignancy in cancers lacking MAGL activity. Together, these findings reveal how cancer cells can co-opt a lipolytic enzyme to translate their lipogenic state into an array of protumorigenic signals.PaperFlick To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon belowHelp with MP4 filesOptionsDownload video (23152 K)

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (297 K)Download as PowerPoint slideHighlights► Monoacylglycerol lipase (MAGL) is elevated in aggressive human cancer cells ► Loss of MAGL lowers fatty acid levels in cancer cells and impairs pathogenicity ► MAGL controls a signaling network enriched in protumorigenic lipids ► A high-fat diet can restore the growth of tumors lacking MAGL in vivo