Creatine Mediated Crosstalk between Adipocytes and Cancer Cells Regulates Obesity-Driven Breast Cancer

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, 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 specifically attenuated obesity-driven tumor growth. Similarly, inhibition of creatine import into cancer cells by knockdown of the creatine transporter (Slc6a8) reduced tumor growth in obesity. In parallel, breast cancer cells in obese animals markedly upregulated the fatty acyl-CoA synthetase, Acsbg1, driving creatine-dependent tumor progression. Analyses of human breast tumors revealed that increased Slc6a8 and Acsbg1 expression were significantly associated with worse tumor grade and that increased Slc6a8 expression was associated with reduced survival in triple negative breast cancer.These findings reveal key nodes in the crosstalk between adipocytes and cancer cells in the tumor microenvironment necessary for obesity-dependent breast cancer progression.