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

Cell Metab. 2021 Mar 2;33(3):499-512.e6. doi: 10.1016/j.cmet.2021.01.018. | PubMed

Olivia A Maguire¹, Sarah E Ackerman², Sarah K Szwed¹, Aarthi V Maganti³, François Marchildon³, Xiaojing Huang⁴, Daniel J Kramer¹, Adriana Rosas-Villegas³, Rebecca G Gelfer⁵, Lauren E Turner³, Victor Ceballos³, Asal Hejazi³, Bozena Samborska⁶, Janane F Rahbani⁶, Christien B Dykstra⁶, Matthew G Annis⁷, Ji-Dung Luo⁸, Thomas S Carroll⁸, Caroline S Jiang⁹, Andrew J Dannenberg¹⁰, Peter M Siegel⁶, Sarah A Tersey¹¹, Raghavendra G Mirmira¹¹, Lawrence Kazak⁶, Paul Cohen¹²

1. Laboratory of Molecular Metabolism, The Rockefeller University, New York, NY 10065, USA; Weill Cornell/Rockefeller/Sloan Kettering Tri-institutional MD-PhD Program, New York, NY 10065, USA.
2. Laboratory of Molecular Metabolism, The Rockefeller University, New York, NY 10065, USA; AAAS Science and Technology Policy Fellow in the Office of Global Health, Health Workforce Branch, U.S. Agency for International Development, Washington, D.C. 20547, USA.
3. Laboratory of Molecular Metabolism, The Rockefeller University, New York, NY 10065, USA.
4. Laboratory of Molecular Metabolism, The Rockefeller University, New York, NY 10065, USA; Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
5. Weill Cornell/Rockefeller/Sloan Kettering Tri-institutional MD-PhD Program, New York, NY 10065, USA.
6. Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montreal, QC H3G1Y6, Canada.
7. Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.
8. Bioinformatics Resource Center, The Rockefeller University, New York, NY 10065, USA.
9. Rockefeller University Hospital, The Rockefeller University, New York, NY 10065, USA.
10. Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
11. Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
12. Laboratory of Molecular Metabolism, The Rockefeller University, New York, NY 10065, USA. Electronic address: pcohen@rockefeller.edu.

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.

Presented By Sarah Ackerman and Olivia Maguire