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

被引：84

作者：

Maguire, Olivia A. ^{[1
,2
]}

Ackerman, Sarah E. ^{[1
,4
]}

Szwed, Sarah K. ^{[1
,2
]}

Maganti, Aarthi V. ^{[1
]}

Marchildon, Francois ^{[1
]}

Huang, Xiaojing ^{[1
,3
]}

Kramer, Daniel J. ^{[1
,2
]}

Rosas-Villegas, Adriana ^{[1
]}

Gelfer, Rebecca G. ^{[2
]}

Turner, Lauren E. ^{[1
]}

Ceballos, Victor ^{[1
]}

Hejazi, Asal ^{[1
]}

Samborska, Bozena ^{[5
,6
]}

Rahbani, Janane F. ^{[5
,6
]}

Dykstra, Christien B. ^{[5
,6
]}

Annis, Matthew G. ^{[5
]}

Luo, Ji-Dung ^{[7
]}

Carroll, Thomas S. ^{[7
]}

Jiang, Caroline S. ^{[8
]}

Dannenberg, Andrew J. ^{[9
]}

Siegel, Peter M. ^{[5
]}

Tersey, Sarah A. ^{[10
]}

Mirmira, Raghavendra G. ^{[10
]}

Kazak, Lawrence ^{[5
,6
]}

Cohen, Paul ^{[1
]}

机构：

[1] Rockefeller Univ, Lab Mol Metab, New York, NY 10065 USA

[2] Weill Cornell Rockefeller Sloan Kettering Triinst, MD PhD Program, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA

[4] US Agcy Int Dev, Hlth Workforce Branch, Off Global Hlth, Washington, DC 20547 USA

[5] McGill Univ, Goodman Canc Res Ctr, Montreal, PQ H3A 1A3, Canada

[6] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada

[7] Rockefeller Univ, Bioinformat Resource Ctr, New York, NY 10065 USA

[8] Rockefeller Univ, Rockefeller Univ Hosp, New York, NY 10065 USA

[9] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA

[10] Univ Chicago, Dept Med, Chicago, IL 60637 USA

来源：

CELL METABOLISM | 2021年 / 33卷 / 03期

基金：

加拿大健康研究院; 美国国家卫生研究院;

关键词：

ACYL-COA SYNTHETASE; BODY-MASS INDEX; METABOLISM; MORTALITY; METAANALYSIS; INHIBITION; FAMILY; COHORT; LINKS;

D O I：

10.1016/j.cmet.2021.01.018

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：499 / +

页数：20

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