STAT2 Controls Colorectal Tumorigenesis and Resistance to Anti-Cancer Drugs

SIMPLE SUMMARY: Despite recent improvements in survival rates, colorectal cancer is still responsible for millions of premature deaths worldwide. A better understanding of the steps that lead from chronic inflammation to cancer progression could offer new therapeutic options and save many lives. The present study aimed to investigate the role of the transcription factor signal transducer and activator of transcription 2 (STAT2) in colorectal cancer by taking advantage of experimental mouse models and three-dimensional tumoroids. Our results indicate that STAT2 promotes colorectal cancer by various mechanisms and that anti-cancer drugs could easily kill tumor cells lacking STAT2. It is conceivable that future therapeutic strategies for colorectal cancer might try to mitigate the actions of STAT2 to improve the treatment outcome in affected patients. ABSTRACT: Colorectal cancer (CRC) is a significant socioeconomic burden in modern society and is accountable for millions of premature deaths each year. The role of signal transducer and activator of transcription 2 (STAT2)-dependent signaling in this context is not yet fully understood, and no therapies targeting this pathway are currently being pursued. We investigated the role of STAT2 in CRC using experimental mouse models coupled with RNA-sequencing (RNA-Seq) data and functional assays with anti-cancer agents in three-dimensional tumoroids. Stat2(−/−) mice showed greater resistance to the development of CRC in both inflammation-driven and inflammation-independent experimental CRC models. In ex vivo studies, tumoroids derived from Stat2(−/−) mice with the multiple intestinal neoplasia (Min) mutant allele of the adenomatous polyposis coli (Apc) locus exhibited delayed growth, were overall smaller and more differentiated as compared with tumoroids from Apc(Min/+) wildtype (WT) mice. Notably, tumoroids from Apc(Min/+) Stat2(−/−) mice were more susceptible to anti-cancer agents inducing cell death by different mechanisms. Our findings clearly indicated that STAT2 promotes CRC and suggested that interventions targeting STAT2-dependent signals might become an attractive therapeutic option for patients with CRC.