cGAS restricts colon cancer development by protecting intestinal barrier integrity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 23; pp. 1 - 12
• Main Authors: Hu, Shuiqing, Fang, Yan, Chen, Xiang, Cheng, Tianlei, Zhao, Miaoqing, Du, Mingjian, Li, Tuo, Li, Minghao, Zeng, Zhiqun, Wei, Yonglong, Gu, Zhimin, Zhang, Conggang, Sun, Lijun, Chen, Zhijian J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 08-06-2021
• Subjects: Adenosine monophosphate; AMP; Animal models; Animals; Anticancer properties; Antitumor activity; Biological Sciences; Cell culture; Cell proliferation; Colitis; Colon; Colon cancer; Colonic Neoplasms - enzymology; Colonic Neoplasms - genetics; Colorectal cancer; Cyclic GMP; Deoxyribonucleic acid; Dextran; Dextrans; DNA; Epithelial cells; Epithelium; Helper cells; Immune system; Inflammatory bowel disease; Integrity; Interferon; Interleukins; Intestinal Mucosa - enzymology; Intestine; Lymphocytes T; Mice; Mice, Knockout; Mucosa; Myeloid-Derived Suppressor Cells - enzymology; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; Sodium sulfate; Stat3 protein; Stem cell transplantation; Stem cells; Stem Cells - enzymology; Stimulators; Th17 Cells - enzymology; Tumor cell lines; Tumors; cGAS; STING; innate immunity; inflammation; colon cancer
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2105747118

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.