RNA Therapeutics Institute; Program in Molecular Medicine
Cancer Biology | Digestive System | Digestive System Diseases | Neoplasms
Little is known about how interactions between diet, immune recognition, and intestinal stem cells (ISCs) impact the early steps of intestinal tumorigenesis. Here, we show that a high fat diet (HFD) reduces the expression of the major histocompatibility complex II (MHC-II) genes in ISCs. This decline in ISC MHC-II expression in a HFD correlates with an altered intestinal microbiome composition and is recapitulated in antibiotic treated and germ-free mice on a control diet. Mechanistically, pattern recognition receptor and IFNg signaling regulate MHC-II expression in ISCs. Although MHC-II expression on ISCs is dispensable for stem cell function in organoid cultures in vitro, upon loss of the tumor suppressor gene Apc in a HFD, MHC-II- ISCs harbor greater in vivo tumor-initiating capacity than their MHC-II+ counterparts, thus implicating a role for epithelial MHC-II in suppressing tumorigenesis. Finally, ISC-specific genetic ablation of MHC-II in engineered Apc-mediated intestinal tumor models increases tumor burden in a cell autonomous manner. These findings highlight how a HFD alters the immune recognition properties of ISCs through the regulation of MHC-II expression in a manner that could contribute to intestinal tumorigenesis.
Cancer Biology, intestinal tumorigenesis, high fat diet, major histocompatibility complex II (MHC-II) genes, intestinal stem cells
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DOI of Published Version
bioRxiv 2020.09.05.284174; doi: https://doi.org/10.1101/2020.09.05.284174. Link to preprint on bioRxiv.
Beyaz S, Ozata DM, Kucukural A, Orkin SH, Yilmaz OH. (2020). Dietary suppression of MHC-II expression in intestinal stem cells enhances intestinal tumorigenesis [preprint]. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1101/2020.09.05.284174. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1818
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