Colorectal cancer is the second most common cause of cancer-related deaths worldwide, according to the World Health Organization. Understanding factors that contribute to the development of colorectal cancer could point to new targets for treating the disease at earlier stages, when survival rates are highest.
Nicholas Markham, MD, PhD, assistant professor of Medicine, and colleagues are exploring how bacteria in the colon may contribute to cancer development. They previously showed that C. diff (Clostridioides difficile) isolated from human colorectal cancer samples accelerated tumorigenesis in the colon in a mouse model of intestinal cancer.
Now, they have combined single-cell RNA sequencing, spatial transcriptomics and immunofluorescence to build a multiomic atlas of gene expression and protein abundance in C. diff-associated colorectal tumorigenesis.
They report in The Journal of Pathology that the protein DMBT1 (Deleted in Malignant Brain Tumors 1) shows striking differences in regulation in areas of the colon with inflammation versus dysplasia (abnormal cellular changes). DMBT1 is a protein with roles in mucosal immune defense and epithelial cell differentiation.
In a mouse model, the researchers found that expression of DMBT1 increases in normal absorptive colon cells exposed to C. diff, but that its expression is reduced in dysplastic areas compared to normal adjacent tissues.
Immunofluorescence studies confirmed that DMBT1 protein was downregulated in dysplastic regions from three mouse models of colonic tumorigenesis and in colorectal precancerous adenomas from human samples. Using mouse and human organoids, the researchers implicated WNT signaling in the downregulation of DMBT1 mRNA and protein.
The findings suggest that loss of DMBT1 could be a mechanistic link between bacterial infection and colorectal cancer development. Further studies will explore how DMBT1 might function to limit tumorigenesis.
Emily Green, a graduate student in the Molecular Pathology and Immunology program, is the first author of the study. Collaborators at Johns Hopkins University School of Medicine contributed to the study. The research was supported by grants from the Department of Veterans Affairs (BX005699, BX002943) and the National Institutes of Health (P30DK058404, P30CA068485, R00CA230192, P50CA236733).