mTORC2 Promotes Tumorigenesis via Lipid Synthesis

• Published in: Cancer cell Vol. 32; no. 6; pp. 807 - 823.e12
• Main Authors: Guri, Yakir, Colombi, Marco, Dazert, Eva, Hindupur, Sravanth K., Roszik, Jason, Moes, Suzette, Jenoe, Paul, Heim, Markus H., Riezman, Isabelle, Riezman, Howard, Hall, Michael N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.12.2017
• Subjects: Animals; Carcinogenesis - metabolism; Carcinoma, Hepatocellular - etiology; Carcinoma, Hepatocellular - metabolism; cardiolipin; Cell Transformation, Neoplastic - metabolism; Fatty Liver - complications; Fatty Liver - metabolism; glycosphingolipid; hepatocellular carcinoma; hepatosteatosis; Humans; Lipids - biosynthesis; Lipogenesis - physiology; Liver Neoplasms - etiology; Liver Neoplasms - metabolism; Mechanistic Target of Rapamycin Complex 2 - metabolism; Mice; Mice, Knockout; mitochondria; mTOR; NAFLD; NASH; oxidative phosphorylation; sphingolipid; NAFLD; sphingolipid; mitochondria; mTOR; glycosphingolipid; hepatosteatosis; NASH; cardiolipin; hepatocellular carcinoma; oxidative phosphorylation
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2017.11.011

Dysregulated mammalian target of rapamycin (mTOR) promotes cancer, but underlying mechanisms are poorly understood. We describe an mTOR-driven mouse model that displays hepatosteatosis progressing to hepatocellular carcinoma (HCC). Longitudinal proteomic, lipidomics, and metabolomic analyses revealed that hepatic mTORC2 promotes de novo fatty acid and lipid synthesis, leading to steatosis and tumor development. In particular, mTORC2 stimulated sphingolipid (glucosylceramide) and glycerophospholipid (cardiolipin) synthesis. Inhibition of fatty acid or sphingolipid synthesis prevented tumor development, indicating a causal effect in tumorigenesis. Increased levels of cardiolipin were associated with tubular mitochondria and enhanced oxidative phosphorylation. Furthermore, increased lipogenesis correlated with elevated mTORC2 activity and HCC in human patients. Thus, mTORC2 promotes cancer via formation of lipids essential for growth and energy production. [Display omitted] •mTORC2 is oncogenic via fatty acid and lipid synthesis•The sphingolipid glucosylceramide is required for tumorigenesis•Cardiolipin enhances OxPhos to satisfy the increased energy needs of tumor cells•Inhibition of mTORC2 is a potential strategy in the treatment of NAFLD or HCC Guri et al. find that mTORC2 promotes de novo fatty acid and lipid synthesis. This pathway is elevated in human liver cancer and drives hepatosteatosis and liver cancer in mice, whereas its inhibition or deletion of Rictor reduces mouse tumors, suggesting this pathway as a therapeutic target in liver cancer.