Grant: Project Grant

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in Canada. Although significant efforts have been employed to understand the etiology of this cancer, the causes of this cancer is still unknown. Recent work has linked bacteria that reside in the gut to CRC, specifically, certain so-called "pathobionts", which are symbiotic members of the gut microbiota that can participate in disease under specific pathological conditions. Indeed, the list of pathobionts that cause CRC is growing, yet their oncogenic mechanisms are only beginning to be understood. To understand the role of the gut microbiota and pathobionts in CRC, we developed mice that harbor genetic mutations commonly associated with CRC. In addition, since inflammatory bowel diseases predispose to CRC, we have also developed mouse models of colitis-associated cancer. Using these mouse models, we show that certain pathobionts promote cancer by interacting with specific dietary factors, the immune system, or by exploiting mutations in specific genes involved in DNA repair. In short, our work is beginning to uncover the mechanisms by which pathobionts interact with specific etiologic factors to promote cancer. Using these animal models, we are now in position to dissect the mechanisms of how different factors promote CRC and develop protocols to reduce CRC incidence in pre-clinical models. We will leverage our expertise on DNA repair, microbiology, diet, and the immune system to explore the role of gut microbiota in CRC development. Our research has the potential to lead to the development of preventative protocols or therapeutics for CRC. In addition, our research has the capacity to develop diagnostics if certain pathobionts are identified to induce CRC under specific conditions. With this new knowledge, we will be in a good position to enable clinical trials to explore the use of antioxidants, or specific dietary interventions to prevent CRC.