mTORC2 promotes tumorigenesis through control of de novo lipid synthesis.
| Evidence tier | C Animal in vivo |
| Study type | 4 - Animal Study |
| Model system | Mouse; cells |
| Journal | Cancer cell |
| Year | 2017 |
| Peer reviewed | Yes |
| Source | DOI 10.1016/j.ccell.2017.11.011 · PMID 29232555 |
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.
| Intervention | Genetic mTOR-driven mouse model |
| Target | mTORC2 |
| Model | Mouse; cells |
| Effect | Hepatic mTORC2 promotes de novo fatty-acid/lipid synthesis (sphingolipids, glycerophospholipids) driving steatosis → hepatocellular carcinoma |