The role of adipocyte G0/G1 switch gene 2 (G0S2) in the crosstalk between cancer cells and adipocytes

Cancer cells are intermingled within a microenvironment consisting of stromal cells, immune cells and a large assortment of extracellular matrix proteins. Bidirectional interactions between cancer cells and their microenvironment govern tumor growth and development. Among the stromal cells present in this microenvironment, adipocytes were reported to up-regulate cancer cells migration and invasion by providing fatty acids to tumor cells. Also, tumor cells were reported to alter adipocyte phenotype notably by increasing lipolysis. Here, we aimed at identifying key adipocyte genes involved in the crosstalk between tumor cells and adipocytes.

Adipose triglyceride lipase (ATGL), CGI-58 (its activator) and G0S2 (one of its inhibitors) are key actors of the first and rate-limiting step of lipolysis. Among them, we observed that G0S2 is the most strongly repressed in adipocytes upon co-culture with cancer cells. During these experiments, we noticed an acidification of the culture medium which we demonstrated to be the main driver of cancer cells-induced lipolysis. We further established that slight acidification of culture medium to pH values similar to those encountered in tumors was sufficient to repress the expression of G0S2 in adipocytes, that this inhibition can be reversed by PPARɣ activators and that CEBPα is involved in this regulation (as revealed through chromatin immunoprecipitation assay). To better characterize the potential implication of G0S2 in cancer progression, we generated adipocytes expressing G0S2 in a doxycycline-dependent way. We observed that re-expression of G0S2 in adipocyte was sufficient to repress lipolysis, to decrease their capacity to stimulate tumor cell migration and to antagonize their pro-survival effect on cancer cells treated with the chemotherapeutic agent doxorubicin.

In order to verify in vivo the relevance of our in vitro data, we decided to use MMTV-PyMT mice because they develop spontaneous tumors in the mammary glands, a tissue rich in adipocytes. PyMT mice overexpressing G0S2 specifically in adipose tissue (PyMT-aP2G0S2) were generated and compared to control PyMT mice for mammary tumor formation. While tumors developed similarly in both models, the incidence of lung metastases was significantly reduced in the PyMT-aP2G0S2 mice.

Our results support a key role for G0S2 in the crosstalk between adipocytes and cancer cells, since the regulation of its expression in adipocytes is sufficient to modulate the phenotype of tumor cells, their resistance to chemotherapeutic agents and their capacity to form metastases in vivo.