TY - JOUR
T1 - Adipocytes reprogram cancer cell metabolism by diverting glucose towards glycerol-3-phosphate thereby promoting metastasis
AU - Mukherjee, Abir
AU - Bezwada, Divya
AU - Greco, Francesco
AU - Zandbergen, Malu
AU - Shen, Tong
AU - Chiang, Chun Yi
AU - Tasdemir, Medine
AU - Fahrmann, Johannes
AU - Grapov, Dmitry
AU - La Frano, Michael R.
AU - Vu, Hieu S.
AU - Faubert, Brandon
AU - Newman, John W.
AU - McDonnell, Liam A.
AU - Nezi, Luigi
AU - Fiehn, Oliver
AU - DeBerardinis, Ralph J.
AU - Lengyel, Ernst
N1 - Funding Information:
We thank all patients at The University of Chicago for donating tissue to this study. We thank F. Coscia and M. Mann (Max Plank Institute of Biochemistry, Martinsried, Bavaria) for help with proteomic analysis, and J. Andrade at the Center for Research Informatics (University of Chicago) for assistance with microarray analysis. This work was supported by the Ann Sol Schreiber award (372898), Colleen’s dream foundation and the DOD pilot award (W81XWH2110376) to A.M., NIH grants (R01CA169604, R35CA264619) awarded to E.L. D.B. is supported by NIH grant F31CA239330. R.J.D. is supported by grants from NIH (R35CA22044901) and by the Howard Hughes Medical Institute. We thank G. Isenberg for editing the paper. Figure 2 b and Supplementary Figs. 2e,f , 5 f and 6a,f were created using BioRender.com.
Funding Information:
We thank all patients at The University of Chicago for donating tissue to this study. We thank F. Coscia and M. Mann (Max Plank Institute of Biochemistry, Martinsried, Bavaria) for help with proteomic analysis, and J. Andrade at the Center for Research Informatics (University of Chicago) for assistance with microarray analysis. This work was supported by the Ann Sol Schreiber award (372898), Colleen’s dream foundation and the DOD pilot award (W81XWH2110376) to A.M., NIH grants (R01CA169604, R35CA264619) awarded to E.L. D.B. is supported by NIH grant F31CA239330. R.J.D. is supported by grants from NIH (R35CA22044901) and by the Howard Hughes Medical Institute. We thank G. Isenberg for editing the paper. Figure and Supplementary Figs. , and were created using BioRender.com.
Funding Information:
There are no potential conflicts of interest. E.L. received funding from Abbvie and Arsenal Bioscience for preclinical research studies unrelated to the submitted paper.
Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2023/9
Y1 - 2023/9
N2 - 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 bidirectional interaction between primary human adipocytes and ovarian cancer (OvCa) cells using multi-platform metabolomics, imaging mass spectrometry, isotope tracing and gene expression analysis. We report that, in OvCa cells co-cultured with adipocytes and in metastatic tumors, a part of the glucose from glycolysis is utilized for the biosynthesis of glycerol-3-phosphate (G3P). Normoxic HIF1α protein regulates the altered flow of glucose-derived carbons in cancer cells, resulting in increased glycerophospholipids and triacylglycerol synthesis. The knockdown of HIF1α or G3P acyltransferase 3 (a regulatory enzyme of glycerophospholipid 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.
AB - 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 bidirectional interaction between primary human adipocytes and ovarian cancer (OvCa) cells using multi-platform metabolomics, imaging mass spectrometry, isotope tracing and gene expression analysis. We report that, in OvCa cells co-cultured with adipocytes and in metastatic tumors, a part of the glucose from glycolysis is utilized for the biosynthesis of glycerol-3-phosphate (G3P). Normoxic HIF1α protein regulates the altered flow of glucose-derived carbons in cancer cells, resulting in increased glycerophospholipids and triacylglycerol synthesis. The knockdown of HIF1α or G3P acyltransferase 3 (a regulatory enzyme of glycerophospholipid 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85169166150&partnerID=8YFLogxK
U2 - 10.1038/s42255-023-00879-8
DO - 10.1038/s42255-023-00879-8
M3 - Article
C2 - 37653041
AN - SCOPUS:85169166150
SN - 2522-5812
VL - 5
SP - 1563
EP - 1577
JO - Nature Metabolism
JF - Nature Metabolism
IS - 9
ER -