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Adipocytes reprogram glucose metabolism in cancer cells promoting metastasis
- Publication Year :
- 2022
- Publisher :
- Cold Spring Harbor Laboratory, 2022.
-
Abstract
- In the tumor microenvironment, adipocytes function as an alternate fuel source for cancer cells. However, whether adipocytes influence macromolecular biosynthesis in cancer cells is unknown. Here, we systematically characterized the bi-directional interaction between primary human adipocytes and ovarian cancer (OvCa) cells using multi-platform metabolomics, imaging mass spectrometry, [13C]-glucose isotope tracing, and gene expression analysis. We report that omental tumor explants and OvCa cells co-cultured with adipocytes divert part of the glucose from glycolysis and TCA cycle towards glycerol-3-phosphate (G3P) synthesis. Normoxic HIF1α protein, stabilized by adipokines, regulate this altered flow of glucose-derived carbons in cancer cells, resulting in increased synthesis of glycerophospholipids (GPL) and triacylglycerols. Blocking adipocyte-induced HIF1α expression increases lipid peroxidation levels in cancer cells and sensitizes them to ferroptosis-mediated cell death. Subsequently, the knockdown of HIF1α or G3P acyltransferase 3 (a regulatory enzyme of GPL synthesis) reduced metastasis in xenograft models of OvCa. In summary, we show that in an adipose-rich tumor microenvironment, cancer cells generate G3P as a precursor for critical membrane and signaling components, thereby promoting metastasis. Targeting biosynthetic processes specific to adipose-rich tumor microenvironments might be an effective strategy against metastasis.
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi...........1487d43d0fa986047602596e5f74500b