cGAS restricts colon cancer development by protecting intestinal barrier integrity

Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel la GMP-AMP cyclique synthase limite le développement d'un cancer du côlon en protégeant l'intégrité de la barrière intestinale

Résumé en anglais

Intestinal barrier plays a key role in maintaining organismal health. Here we find cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) deficiency compromises intestinal epithelial barrier and exacerbates inflammation. cGAS-deficient mice were highly susceptible to colitis-associated colon cancer (CAC) but not sporadic colon cancer. Surprisingly, the role of cGAS in this process appears to be independent of stimulator of interferon genes (STING)-induced type I interferon signaling, because mice lacking STING or type I interferon receptor were less susceptible to CAC than those lacking cGAS. cGAS but not STING is highly expressed in intestinal stem cells. These results suggest that cGAS has a unique role in protecting the intestinal epithelial barrier and preventing colon cancer development.The DNA-sensing enzyme cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) regulates inflammation and immune defense against pathogens and malignant cells. Although cGAS has been shown to exert antitumor effects in several mouse models harboring transplanted tumor cell lines, its role in tumors arising from endogenous tissues remains unknown. Here, we show that deletion of cGAS in mice exacerbated chemical-induced colitis and colitis-associated colon cancer (CAC). Interestingly, mice lacking cGAS were more susceptible to CAC than those lacking stimulator of interferon genes (STING) or type I interferon receptor under the same conditions. cGAS but not STING is highly expressed in intestinal stem cells. cGAS deficiency led to intestinal stem cell loss and compromised intestinal barrier integrity upon dextran sodium sulfate-induced acute injury. Loss of cGAS exacerbated inflammation, led to activation of STAT3, and accelerated proliferation of intestinal epithelial cells during CAC development. Mice lacking cGAS also accumulated myeloid-derived suppressive cells within the tumor, displayed enhanced Th17 differentiation, but reduced interleukin (IL)-10 production. These results indicate that cGAS plays an important role in controlling CAC development by defending the integrity of the intestinal mucosa.All study data are included in the article and SI Appendix.