Over the last 20 years, my research has examined carcinogenesis with the goal of discovering the mechanistic underpinnings of how diet and lifestyle approaches prevent cancer. In this context, my group has developed and characterized animal models for the early stages of carcinogenesis and we have conducted “omic” analyses to understand what controls formation of a healthy intestinal epithelium and how vitamin D influences colon and prostate epithelial cell biology. 

Our research on the prevention of early-stage prostate cancer used two different prostate-specific VDR KO models and dietary vitamin D deficiency to show that low vitamin D signal alters prostate epithelial cell biology and accelerates early-stage prostate cancer. In addition, we used ChIP-seq to show that there are many vitamin D target genes, controlling a wide array of cell functions, in prostate epithelial cells. 

Data from Fleet et al. (2019) Cancer Prevention Research

Another part of my research is that we have developed a novel transgenic mouse model that limits Cre recombinase expression to the lower bowel (Car1-Cre).  When used to delete an Apc allele, mice develop adenomas exclusively in the distal colon.  In addition, Dextran Sulfate Sodium (DSS)-induced colitis increases the incidence and number of Apc-mutation driven colon tumors because DSS induces colonic Cre transgene expression in this model. We used this model to show that colon cancer is more aggressive when Kras and Apc mutations are combined. Our transgenic mouse is the only animal model available that limits transgene expression to the distal colon with no involvement of the small intestine.  As such, this model is useful for studying agents that alter the course of colon carcinogenesis.

Data from Xue et al. (2010) Mol Prevention Research

In the past several years, we have generated new data showing that vitamin D signaling influences cells of the innate immune system in ways that will influence cancer development. First, we have learned that that high vitamin D signaling can suppress DSS-induced colitis, a potent promoter of colon cancer. Our data suggest that this is due to vitamin D effects on monocytes and macrophages that blunt proinflammatory signaling.  Second, we have observed that vitamin D signaling reduces the ability of myeloid derived suppressor cells (MDSC) to protect tumor cells from clearance by cytotoxic T cells.  MDSC normally allow tumors to become established, grow, and metastasize and so our findings suggest that vitamin D could be used as an adjunct to immunotherapy.

Data from Wang et al. (2017) Endocrinology Data from Fleet et al. (2019) J Steroid Biochem Mol Biol