Person:

Ricoult, Stephane Jean Hermann

Eukaryotic cells coordinately control anabolic and catabolic processes to maintain cell and tissue homeostasis. Mechanistic target of rapamycin complex 1 (mTORC1) promotes nutrient-consuming anabolic processes, such as protein synthesis1. Here we show that as well as increasing protein synthesis, mTORC1 activation in mouse and human cells also promotes an increased capacity for protein degradation. Cells with activated mTORC1 exhibited elevated levels of intact and active proteasomes through a global increase in the expression of genes encoding proteasome subunits. The increase in proteasome gene expression, cellular proteasome content, and rates of protein turnover downstream of mTORC1 were all dependent on induction of the transcription factor nuclear factor erythroid-derived 2-related factor 1 (NRF1; also known as NFE2L1). Genetic activation of mTORC1 through loss of the tuberous sclerosis complex tumour suppressors, TSC1 or TSC2, or physiological activation of mTORC1 in response to growth factors or feeding resulted in increased NRF1 expression in cells and tissues. We find that this NRF1-dependent elevation in proteasome levels serves to increase the intracellular pool of amino acids, which thereby influences rates of new protein synthesis. Therefore, mTORC1 signalling increases the efficiency of proteasome-mediated protein degradation for both quality control and as a mechanism to supply substrate for sustained protein synthesis.

The sterol regulatory element binding protein (SREBP) transcription factors have emerged as central regulators of de novo lipogenesis in the liver. However, while it is known that lipid synthesis is elevated in many cancers, much less is known about the control of lipid metabolism in this context. The goals of this dissertation were to better understand the mechanisms through which commonly mutated oncogenes and tumor suppressors promote de novo lipid synthesis, and to further define the importance of this process in cancer.

Using isogenic oncogene-expressing breast epithelial cells and breast cancer cell lines, I have identified a major mechanism through which two of the most commonly activated oncogenes in cancer promote de novo lipogenesis. In particular, I found that the expression of oncogenic PI3K or K-Ras is sufficient to stimulate de novo lipid synthesis in breast epithelial cells through the activation of mechanistic target of rapamycin complex 1 (mTORC1) and SREBP. Consistent with these findings, increased mTORC1 signaling in breast cancer patient tumor samples is associated with elevated expression of canonical SREBP targets involved in de novo lipogenesis. I further demonstrate that SREBP depletion in breast cancer cells or in oncogene-expressing epithelial cells reduces growth-factor independent proliferation.

To better understand the role of SREBP in cancer metabolism, I sought to determine whether SREBP regulates isocitrate dehydrogenase 1 (IDH1), which is both a metabolic enzyme and an oncogene. Specifically, I show that SREBP activates the expression of IDH1 across a panel of cancer cell lines from different lineages, and that IDH1 expression facilitates the flux of glutamine-derived carbons towards de novo lipid synthesis. In addition, SREBP stimulates the expression of oncogenic IDH1R132C, which is a neomorphic enzyme that produces the oncometabolite 2-hydroxyglutarate, and can regulate 2-hydroxyglutarate production in mutant-IDH1 cells.

Collectively, these studies expand our understanding of lipid metabolism in cancer and identify important roles for SREBP in cancer cell metabolism and proliferation. Our results will help guide future studies on the regulation of SREBP, the role of SREBP targets, and the production of specific lipid species in cancer, which will hopefully identify novel therapeutic targets to treat cancer patients.