Susceptibility to inflammatory bowel diseases promotes invasive carcinomas in a murine model of ATF6-driven colon cancer
J Crohns Colitis article with contribution from Barbara Schraml
03.07.2025
Kövilein J, Sorbie A, Khaloian S, Küntzel V, von Stern M, Ahmed M, Jarosch S, Remke M, Metwaly A, Reuss EM, Busch DH, Allez M, Steiger K, Schraml B, Coleman OI, Haller D. Susceptibility to inflammatory bowel diseases promotes invasive carcinomas in a murine model of ATF6-driven colon cancer. J Crohns Colitis. 2025 Jul 3;19(7):jjaf102. doi: 10.1093/ecco-jcc/jjaf102.
Abstract (cited directly from the article):
Background and aims
Chronic inflammation in inflammatory bowel disease (IBD) patients represents a risk factor for developing colitis-associated cancer (CAC). We previously linked the endoplasmic reticulum unfolded protein response (UPRER) signal transducer activating transcription factor 6 (ATF6) with spontaneous microbiota-dependent colonic adenoma development in mice expressing epithelial-specific activated ATF6 (nATF6IEC).
Methods
To investigate IBD-related risk factors in ATF6-mediated tumorigenesis, we crossed tumor-free monoallelic (tg/wt) nATF6IEC mice with interleukin-10 deficient mice (Il10-/-). We characterized our newly generated murine model under germ-free (GF) and specific pathogen-free (SPF) conditions, including tumor phenotype and immune cell characterizations, as well as complex human stool and minimal consortium colonizations.
Results
IL-10 deficiency initiated tumor susceptibility, with 77% of 12-week tg/wt;Il10-/- mice developing colonic adenomas and invasive carcinomas in this novel CAC mouse model. Tumor formation correlated with mucosal immune cell infiltration, characterized by CD11b+ granulocytes and monocytes, and mucosa-associated dysbiosis. Colonization of germ-free nATF6IEC;Il10-/- mice with minimal biosynthetic consortia and IBD stool re-established CAC, confirming microbiota-dependent ATF6-driven tumorigenesis. Increased ATF6 expression in IBD patients during active disease highlights human relevance.
Conclusion
Our findings show that IBD susceptibility heightens the risk for ATF6-driven tumorigenesis.
