Grant: Fellowship: Jean-François St-Denis (Prize)

Colorectal cancer is the third most common malignancy worldwide and a major cause of cancer-related death. Cancer is driven by genetic mutations, and the most common mutation in colorectal cancer is inactivation of tumor suppressor gene adenomatous polyposis coli (APC). APC is an important regulator of intestinal epithelial cell self-renewal. Mutated APC results in uncontrolled intestinal epithelial cell proliferation and spontaneous development of intestinal tumors in mice. People with hereditary APC mutations, known as familial adenomatous polyposis, are predisposed to colorectal cancer. Previous research from our laboratory showed that colorectal tumors, from both human and mouse, have defective epithelial barrier that becomes leaky. This results in the penetration of commensal microbes and their products from the intestinal track into surrounding tissues. Importantly, the leakage of microbial products elicits a specific tumor-promoting inflammatory response that corresponds with poor patient survival. Yet, it remains unclear how epithelial barrier in intestinal tumors first becomes defective. My proposed research aims to identify the reason(s) which cause defective intestinal epithelial barrier development in colorectal cancer using mice with APC mutation as a model, through which we can develop therapeutics and/or preventatives that address the defects in intestinal epithelia to help colorectal cancer patients.