STAT2 Controls Colorectal Tumorigenesis and Resistance to Anti-Cancer Drugs

• Published in: Cancers Vol. 15; no. 22; p. 5423
• Main Authors: Chiriac, Mircea T, Hracsko, Zsuzsanna, Becker, Christoph, Neurath, Markus F
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.11.2023
• Subjects: Adenomatous polyposis coli; Analysis; Animal models; Antimitotic agents; Antineoplastic agents; Antitumor agents; Cancer; Cancer therapies; Cell death; Colorectal cancer; Colorectal carcinoma; Development and progression; Drug resistance; Drug therapy; Endoscopy; Ethylenediaminetetraacetic acid; Growth factors; Health aspects; Homeostasis; Inflammation; Inflammatory bowel disease; Interferon; Kinases; Medical research; Melanoma; Mice; Polyposis coli; RNA; RNA sequencing; Scientific equipment and supplies industry; Stat2 protein; Tumor cells; Tumor necrosis factor-TNF; Tumorigenesis; Tumors; United States; Netherlands; Germany; United States > US
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers15225423

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 ApcMin/+ wildtype (WT) mice. Notably, tumoroids from ApcMin/+ 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.