A novel mouse model we constructed (villin-cre, Msh2flox/flox, TgfbrII?humanized? ) faithfully recapitulates mutations and a key genetic circuit driving defective mismatch repair tumorigenesis. In this model we established feeding a higher risk purified western style diet is necessary to produce tumors in the colon rather than mainly in the small intestine, therefore completely mimicking interaction of nutritional and genetic risk factors for human colon cancer. Our goals are to: a) use an approach of partial repletion of dietary alterations to identify which components of the diet impact the development of colon tumors in this VcMshThu model; b) use single cell RNAseq, now routine in our group, to dissect the dietary induced cellular and transcriptional remodeling of the colonic mucosa by the multiple diets to determine which aspects of remodeling of the colonic mucosa by the dietary factors promote tumor development in the colon. The data will provide unprecedented understanding of which and how key common dietary components in the human western style diet of developed countries promote higher risk for colon tumor development, and the complex cellular and molecular remodeling of the colonic mucosa of the western diet and components that promote development of these tumors. The translational potential is development of much deeper understanding of mechanisms establishing risk for CRC, and thus identification of new early markers of risk. This can inform cost effective strategies for screening and more efficacious new strategies for intervention.
We established a mouse model faithfully reproducing interactions between the modern western-style diet and mutations in a key genetic circuit that cause a significant fraction of colon cancer in the US and other developed countries. We will determine contribution of each of 3 groups of nutrients in the western diet (vitamin D3 and calcium; donors to single carbon metabolism; and fiber) to colon tumor development, and use single cell RNA sequencing to determine how the diet, and each dietary subset, remodels the cell and molecular biology of the colonic tissue in causing colon tumors. This will provide unprecedented insight into dietary driven mechanisms determining risk for colon cancer, informing strategies for early detection of risk and efficacious intervention.
