Acidosis-induced regulation of adipocyte G0S2 promotes the crosstalk between adipocytes and cancer cells as well as tumor progression.

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 cell 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 cell-induced lipolysis. This prompted us to evaluate the effect of acidosis on gene expression in adipocytes. G0S2 expression was repressed upon acidification to pH values commonly observed in the tumor microenvironment. We demonstrated that the inhibition of G0S2 expression can be reversed by PPARgamma activators, and showed, by chromatin immunoprecipitation experiments, that CEBP/alpha is involved in G0S2 regulation. To further analyze the role of G0S2, 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 the pro-migratory effect exerted by adipocyte on cancer cells and, most importantly, to antagonize the pro-survival effect exerted by adipocytes on cancer cells treated with the chemotherapeutic agent doxorubicin. In vivo, the specific overexpression of G0S2 in the adipose tissues of MMTV-PyMT mice decreased tumor growth and metastasis formation.
Our results highlight new cellular regulations induced by tumor acidosis and describe how they alter the crosstalk between cancer cells and their microenvironment as well as tumor progression.