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Creatine-mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancer.

Citation
Maguire, O. A., et al. “Creatine-Mediated Crosstalk Between Adipocytes And Cancer Cells Regulates Obesity-Driven Breast Cancer.”. Cell Metabolism, pp. 499-512.e6.
Center University of Chicago
Author Olivia A Maguire, Sarah E Ackerman, Sarah K Szwed, Aarthi Maganti V, François Marchildon, Xiaojing Huang, Daniel J Kramer, Adriana Rosas-Villegas, Rebecca G Gelfer, Lauren E Turner, Victor Ceballos, Asal Hejazi, Bozena Samborska, Janane F Rahbani, Christien B Dykstra, Matthew G Annis, Ji-Dung Luo, Thomas S Carroll, Caroline S Jiang, Andrew J Dannenberg, Peter M Siegel, Sarah A Tersey, Raghavendra G Mirmira, Lawrence Kazak, Paul Cohen
Keywords Acsbg1, Gatm, breast cancer, creatine, hypoxia, obesity
Abstract

Obesity is a major risk factor for adverse outcomes in breast cancer; however, the underlying molecular mechanisms have not been elucidated. To investigate the role of crosstalk between mammary adipocytes and neoplastic cells in the tumor microenvironment (TME), we performed transcriptomic analysis of cancer cells and adjacent adipose tissue in a murine model of obesity-accelerated breast cancer and identified glycine amidinotransferase (Gatm) in adipocytes and Acsbg1 in cancer cells as required for obesity-driven tumor progression. Gatm is the rate-limiting enzyme in creatine biosynthesis, and deletion in adipocytes attenuated obesity-driven tumor growth. Similarly, genetic inhibition of creatine import into cancer cells reduced tumor growth in obesity. In parallel, breast cancer cells in obese animals upregulated the fatty acyl-CoA synthetase Acsbg1 to promote creatine-dependent tumor progression. These findings reveal key nodes in the crosstalk between adipocytes and cancer cells in the TME necessary for obesity-driven breast cancer progression.

Year of Publication
2021
Journal
Cell metabolism
Volume
33
Issue
3
Number of Pages
499-512.e6
Date Published
03/2021
ISSN Number
1932-7420
DOI
10.1016/j.cmet.2021.01.018
Alternate Journal
Cell Metab
PMID
33596409
PMCID
PMC7954401
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