[en] Bidirectional interactions between cancer cells and their microenvironment govern tumor progression. Among the stromal cells in this microenvironment, adipocytes have been reported to upregulate cancer cell migration and invasion by producing fatty acids. Conversely, cancer cells alter adipocyte phenotype notably via increased lipolysis. We aimed to identify the mechanisms through which cancer cells trigger adipocyte lipolysis and evaluate the functional consequences on cancer progression. Here, we show that cancer cell-induced acidification of the extracellular medium strongly promotes preadipocyte lipolysis through a mechanism that does not involve lipophagy but requires adipose triglyceride lipase (ATGL) activity. This increased lipolysis is triggered mainly by attenuation of the G0/G1 switch gene 2 (G0S2)-induced inhibition of ATGL. G0S2-mediated regulation in preadipocytes affects their communication with breast cancer cells, modifying the phenotype of the cancer cells and increasing their resistance to chemotherapeutic agents in vitro. Furthermore, we demonstrate that the adipocyte-specific overexpression of G0S2 impairs mammary tumor growth and lung metastasis formation in vivo. Our results highlight the importance of acidosis in cancer cell-adipocyte crosstalk and identify G0S2 as the main regulator of cancer-induced lipolysis, regulating tumor establishment and spreading.
Brohée, Laura; Laboratory of Connective Tissues Biology, GIGA-Cancer, University of Liège, Avenue Hippocrate 13, 4000, Liège, Belgium
Dupont, Laura ; Université de Liège - ULiège > GIGA > GIGA Cancer - Connective Tissue Biology
Lefevre, Camille; Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Avenue Mounier 73, B1.73.11, 1200, Brussels, Belgium
Peiffer, Raphaël ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Saarinen, Alicia M; Department of Biochemistry and Molecular Biology, Mayo Clinic in Arizona Scottsdale, AZ, USA
Peulen, Olivier ; Université de Liège - ULiège > GIGA > GIGA Cancer - Metastases Research Laboratory
Bindels, Laure; Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Avenue Mounier 73, B1.73.11, 1200, Brussels, Belgium
Liu, Jun; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
Colige, Alain ; Université de Liège - ULiège > GIGA > GIGA Cancer - Connective Tissue Biology
Deroanne, Christophe ; Université de Liège - ULiège > GIGA > GIGA Cancer - Connective Tissue Biology
Language :
English
Title :
Acidosis-induced regulation of adipocyte G0S2 promotes crosstalk between adipocytes and breast cancer cells as well as tumor progression.
Roles and regulatory mechanisms of adipocytic lipolysis during tumour progression.
Funders :
F.R.S.-FNRS - Fund for Scientific Research [BE] ULiège - Université de Liège [BE] Fonds Léon Fredericq [BE]
Funding number :
7.6507.21
Funding text :
J.C. and C.F.D. were supported by grants from the Léon Frédericq Foundation and the University of Liège, respectively. J.C. is a doctoral fellow from the Televie (7.6507.21). L.D. is a postdoctoral researcher, A.C. is a Senior Research Associate, and C.F.D. is a Research Associate at the Belgian F.R.S.-FNRS.
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