mTORC2 Promotes Tumorigenesis via Lipid Synthesis

Cancer cells adapt rapidly to metabolic changes in order to maintain growth. We provide first evidence that the evolutionary conserved kinase Target of Rapamycin (TOR) in cancer cells orchestrate metabolic adaptation via de-novo lipid synthesis, thereby promoting growth. Mechanistically, mTOR Complex 2 (mTORC2) transcriptionally stimulates de-novo fatty acid synthesis via Sterol Regulatory Element-Binding Protein-1c (SREBP1c), thereby providing building blocks required for complex lipids synthesis, such as glycosphingolipids and cardiolipins. While glycosphingolipids are essential structural components for a growing cell, the mitochondrial phospholipid cardiolipin is essential for oxidative phosphorylation. Improved mitochondrial activity is essential to satisfy the increased energetic need of rapidly growing cells. Thus, mTORC2 is tumorigenic via lipids synthesis. Cancer patients exhibiting high mTORC2 signaling may benefit from lipogenesis blocking therapies.