mTORC2 Promotes Tumorigenesis via Lipid Synthesis

Cancer Cell. 2017 Dec 11;32(6):807-823.e12. 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.

Keywords: NAFLD; NASH; cardiolipin; glycosphingolipid; hepatocellular carcinoma; hepatosteatosis; mTOR; mitochondria; oxidative phosphorylation; sphingolipid.

MeSH terms

  • Animals
  • Carcinogenesis / metabolism*
  • Carcinoma, Hepatocellular / etiology
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Transformation, Neoplastic / metabolism
  • Fatty Liver / complications
  • Fatty Liver / metabolism*
  • Humans
  • Lipids / biosynthesis
  • Lipogenesis / physiology*
  • Liver Neoplasms / etiology
  • Liver Neoplasms / metabolism*
  • Mechanistic Target of Rapamycin Complex 2 / metabolism*
  • Mice
  • Mice, Knockout


  • Lipids
  • Mechanistic Target of Rapamycin Complex 2