mTORC2 promotes tumor growth via lipid synthesis

Dysregulated mammalian TOR (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, lipidomic and metabolomic analyses revealed that hepatic mTORC2 promotes de novo fatty acid and lipid synthesis, and thereby tumorigenesis. In particular, mTORC2 stimulated sphingolipid (glucoceramide) and glycerophospholipid (cardiolipin) synthesis. Inhibition of fatty acid or sphingolipid synthesis prevented tumor development. Increased levels of cardiolipin were associated with tubular mitochondria and enhanced oxidative phosphorylation. Thus, mTORC2 promotes cancer via formation of lipids essential for growth and energy production. Collectively, these findings illustrate a role for mTORC2 in lipid-mediated oncogenesis that could be exploited for targeted cancer therapies.