Projects - MEDOC

Metabolic dysregulation, an important manifestation of inflammation, may hold the key for addressing the growing problem of Early-Onset CRC (EOCRC) (i.e., <50 years), and numerous other obesity-related cancers. The proposed work draws on experience that we have accumulated in working with inflammation, and metabolic dysregulation in particular, in both laboratory animal experiments and human studies and that have contributed many hundreds of papers and thousands of citations to the medical literature over the last 10 years. Results from this work, which meld our wide-ranging experience in transdisciplinary science, have important implications for advancing the science and real, practical implications for addressing cancer-related disparities that have consistently disfavor African Americans, a group that is uniquely metabolically obese (i.e., evince symptoms associated with obesity at lower levels of overall adiposity).

Data obtained from this proposal are expected to establish A-FABP as a novel therapeutic target and biomarker for HFD-induced obesity/breast cancer risk. This proposal will not only have basic science ramifications for understanding how A-FABP shapes dysregulated lipid metabolism and functions of TAMs and breast cancer cells, but will also have significant clinical implications for prevention and immunotherapy of obesity-associated breast cancer.

Obesity is broadly associated with both increased incidences of a variety of cancers and a chronic inflammatory state. Our interdisciplinary team with expertise in cancer, obesity, microbiome, immunometabolism will test if obesity-altered gut microbes enhance cancer risk through dysregulated protective immunity which leads to changes in the immune milieu that increase cancer cell transformation and initiation. These studies will increase understanding of obesity-associated cancer risk and point to potential interventions to alleviate this risk or treat existing cancers.

Ceramides are products of fat and protein metabolism that accumulate in individuals with obesity or dyslipidemia and are strongly linked to insulin resistance. Herein we propose to leverage large-scale epidemiologic and clinical cohorts to identify associations of ceramides with colorectal cancer risk, and animal experiments to study the efficacy of new ceramide-lowering interventions. Our study will clarify the key role of ceramides in the metabolic dysregulation underlying colorectal cancer and identify new targets for colorectal cancer prevention.

Evidence collectively implicates visceral adiposity and its closely related metabolic dysregulation as a causal driver of obesity-related colorectal and liver cancers. Inflammation has been proposed as a mediating factor, but the precise inflammatory pathways that best describe the metabolically unhealthy obese state are unknown, warranting well-phenotyped large prospective cohort studies Thus, novel approaches for distilling the inflammatory pathways and markers to identify those most reflective of the metabolically unhealthy obese state have immense potential to uncover key mechanisms and inform powerful broad-spectrum strategies for preventing these cancers.

The Metabolic Dysregulation and Cancer Risk Consortium (MDCRC) is being created to study the biologic mechanisms by which obesity increases the risk of cancer in humans and will bring together several research groups studying how obesity alters normal metabolic pathways leading to cancer risk. The Consortium members will work together to identify common areas of data collection, and develop of a harmonized data set to accelerate research and discovery. The MDCRC Coordinating Center will facilitate the creation of this rich research data set, as well as provide both scientific leadership and project management for the collaborative cross-Consortium activities.