Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis.
Tumor 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:
Nomura
Daniel K
DK
The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Long
Jonathan Z
JZ
Niessen
Sherry
S
Hoover
Heather S
HS
Ng
Shu-Wing
SW
Cravatt
Benjamin F
BF
D000818:Animals; D002460:Cell Line; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D008994:Monoacylglycerol Lipases / Q000235:genetics / Q000378:metabolism*; D050178:Monoglycerides / Q000378:metabolism; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D005227:Fatty Acids; D050178:Monoglycerides; D008994:Monoacylglycerol Lipases