Adipocytes reprogram cancer cell metabolism by diverting glucose towards glycerol-3-phosphate thereby promoting metastasis

Authors: MUKHERJEE, ABIR - University Of Chicago; BEZWADA, DIVYA - University Of Texas Southwestern Medical Center; GRECO, FRANCESCO - Institute Of Life Science, Scuola Superiore Sant'Anna; ZANDBERGEN, MALU - University Of Chicago; SHEN, TONG - University Of California, Davis; CHIANG, CHUN-YI - University Of Chicago; TASDEMIR, MEDINE - University Of Chicago; FAHRMANN, JOHANNES - University Of California, Davis; GRAPOV, DMITRY - University Of California, Davis; LA FRANO, MICHEAL - University Of California, Davis; VU, HIEU - University Of Texas Southwestern Medical Center; FAUBERT, BRANDON - University Of Chicago; Newman, John; MCDONNELL, LIAM - Institute Of Life Science, Scuola Superiore Sant'Anna; NEZI, LUIGI - (NCE, CECR)networks Of Centres Of Exellence Of Canada, Centres Of Excellence For Commercilization A; FIEHN, OLIVER - University Of California, Davis; DEBERARDINIS, RALPH - University Of Texas Southwestern Medical Center; LENGYEL, ERNST - University Of Chicago

Submitted to: Cell Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/27/2023
Publication Date: 8/31/2023
Citation: Mukherjee, A., Bezwada, D., Greco, F., Zandbergen, M., Shen, T., Chiang, C., Tasdemir, M., Fahrmann, J., Grapov, D., La Frano, M.R., Vu, H.S., Faubert, B., Newman, J.W., Mcdonnell, L.A., Nezi, L., Fiehn, O., Deberardinis, R., Lengyel, E. 2023. Adipocytes reprogram cancer cell metabolism by diverting glucose towards glycerol-3-phosphate thereby promoting metastasis. Cell Metabolism. https://doi.org/10.1038/s42255-023-00879-8.
DOI: https://doi.org/10.1038/s42255-023-00879-8

Interpretive Summary: Several intra-abdominally metastasizing cancers have a propensity to seed to adipose (i.e. fat) tissues in the abdominal cavity, including colorectal and ovarian cancers. It is known that the adipose tissue provides lipids as a source of energy for the growing tumor cells, but if interactions with adipose cells has additional impacts on cancer cell metabolism is not known. To investigate this question, adipose and ovarian cancer cells were grown alone or together. Differences in gene expression, broad swaths of metabolites and the movement of glucose-derived carbon atoms into down stream products were evaluated. It was found that adipocytes redirect glucose utilization in cancer cells from energy towards lipid membrane and storage through a “pseudo-hypoxia” response that promotes ovarian cancer cell aggressiveness.

Technical Abstract: Adipocytes function as a source of lipids in the tumor microenvironment, fueling cancer growth through ß–oxidation, but it is unclear whether the interaction of adipocytes with cancer cells has additional metabolic functions in tumor cells. We describe the systematic characterization of the bi-directional interactions between adipocytes and cancer cells, using multi-platform metabolomics, [ 13 C]-glucose isotope tracing, and microarray analysis. Adipocytes divert glucose from glycolysis towards synthesis of glycerol-3-phosphate in cancer cells and tumor explants, resulting in glycerophospholipids and triacylglycerol synthesis. Primary human omental adipocytes mediate these metabolic changes through the normoxic induction of HIF1a expression in cancer cells. Knockdown of HIF1a or GPAT3, the regulatory enzyme of the glycerophospholipid synthesis pathway, reduces metastasis in xenograft models of ovarian cancer. In summary, we show that adipocytes divert glucose towards glycerophospholipid synthesis, precursor to critical membrane and signaling components, and away from the central carbon pathway of glycolysis and TCA cycle, thereby promoting metastasis.