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

TitleCreatine-mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancer.
Publication TypeJournal Article
Year of Publication2021
AuthorsMaguire OA, Ackerman SE, Szwed SK, Maganti AV, Marchildon F, Huang X, Kramer DJ, Rosas-Villegas A, Gelfer RG, Turner LE, Ceballos V, Hejazi A, Samborska B, Rahbani JF, Dykstra CB, Annis MG, Luo J-D, Carroll TS, Jiang CS, Dannenberg AJ, Siegel PM, Tersey SA, Mirmira RG, Kazak L, Cohen P
JournalCell Metab
Date Published2021 Feb 10
ISSN1932-7420
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.

DOI10.1016/j.cmet.2021.01.018
Alternate JournalCell Metab
PubMed ID33596409
Grant ListP30 DK020595 / DK / NIDDK NIH HHS / United States
R01 DK060581 / DK / NIDDK NIH HHS / United States
R01 DK124906 / DK / NIDDK NIH HHS / United States

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