A Transdisciplinary Approach to Investigating Metabolic Dysregulation in Obese Parent and Child Dyads and Risk of Colorectal Cancer - admin supplement

PROJECT SUMMARY Obesity increases the risk for colorectal cancer (CRC). Indeed, epidemiological studies have found a strong link between a poor diet and colorectal cancer and experimental studies in mice substantiate these claims. Because adiposity and diet drive metabolic dysregulation, we posit that understanding the interaction between diet and

adiposity are key to understanding the genesis of CRC (as well as other obesity-related cancers). The insulin/insulin-like growth factor (IGF) system, which is dysregulated in obesity and functions on a pro- inflammatory substrate, is a major determinant in the pathogenesis and progression of CRC. Low-grade, chronic

systemic inflammation (i.e., meta-inflammation) associated with obesity – is inextricably linked to these metabolic derangements. Indeed, inflammatory mediators contribute to metabolic dysfunction, including increases in circulating cytokines, decreases in protective factors like adiponectin, and communication between inflammatory

and metabolic cells. Consumption of pro-inflammatory, energy-dense, often high-fat diets modulate microbiota and induce alterations in intestinal barrier function that is associated with an increase in low-grade inflammation and insulin resistance. Thus, gut microbes are likely at the epicenter of the obesity-meta-inflammation-CRC link.

Diet is the most influential factor on gut microbe composition and function and therefore presents a strategy for intervention including natural products as dietary supplements. Cannabinoids have received recent attention for their potential health benefits. In fact, the NCI is supporting research on the potential for cannabinoids in cancer

related outcomes. Excitingly, preliminary data that we have collected shows that cannabis administered to obese mice improves the homeostasis model of risk assessment-insulin resistance (HOMA-IR) and reduces adipose tissue inflammation and pro-inflammatory macrophages without changes in body weight. These outcomes have

been associated with CRC progression and have been linked to changes to the gut microbiome. As such, this Diversity Supplement will test the hypothesis that the cannabis plant can reduce meta-inflammation and subsequent metabolic dysfunction in obesity-associated CRC, and this will be mediated via its actions on gut

microbes. Under this award Christian will 1) achieve training in cutting edge techniques related to metabolic dysregulation and cancer risk including extensive training in mouse models of cancer, in immune profiling, and in assessing microbiome and metabolite signatures, as well as in professional development training; 2) publish

1 first author paper and 2 co-author papers for each year of the award; 3) achieve training in career development; and 4) contribute to the MeDOC consortium. Funding from this Diversity Supplement, mentoring from Dr. Murphy and support from the other REMEDY investigators (advisory committee: Drs. Hebert, Hofseth, Velazquez,

Kubinak, and Li), the MeDOC consortium, and the resources at the University of South Carolina will allow Christian to achieve his goal of becoming an independent investigator focused on metabolic dysregulation and cancer risk.