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bioRxiv · 10.1101/2024.11.25.624835

Susceptibility to inflammatory bowel diseases promotes invasive carcinomas in a murine model of ATF6-driven colon cancer

Kövilein, J.·Sorbie, A.·Khaloian, S.·Küntzel, V.·Ahmed, M.·Jarosch, S.·Remke, M.·Metwaly, A.·Reuss, E. M.·Busch, D.·Allez, M.·Steiger, K.·Schraml, B.·Coleman, O. I.·Haller, D.
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Abstract

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). 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-/-). IL10 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 its human relevance. Our findings show that IBD susceptibility heightens the risk for ATF6-driven tumorigenesis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/624835v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@17e280eorg.highwire.dtl.DTLVardef@177ceacorg.highwire.dtl.DTLVardef@a1916borg.highwire.dtl.DTLVardef@152374f_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Kövilein, J., Sorbie, A., Khaloian, S., Küntzel, V., Ahmed, M., Jarosch, S., Remke, M., Metwaly, A., Reuss, E. M., Busch, D., Allez, M., Steiger, K., Schraml, B., Coleman, O. I., Haller, D.. 2024-11-26. Susceptibility to inflammatory bowel diseases promotes invasive carcinomas in a murine model of ATF6-driven colon cancer. https://doi.org/10.1101/2024.11.25.624835

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