UC Irvine

Cancer is one of the leading causes of death in the United States, with cachexia presenting as a near ubiquitous complication of cancer that severely impacts patient quality of life and patient survival. Cancer cachexia is characterized as a metabolic syndrome that results with the progressive atrophy of patient skeletal muscle and fat tissue that is independent of starvation. The mechanism for cachexia induction is complex, involving a tumor driven catabolic cascade across all organs and tissues. Metabolic reprogramming is a hallmark of cancer essential to tumor initiation, progression and the development of cancer associated comorbidities like cancer cachexia. In addition to the Warburg effect, evidence reveals that glutamine and ketone metabolism play important roles in tumorigenesis, particularly in the context of colorectal cancer. While the effects of these two metabolic pathways have been studied in the context of tumor growth, the impact of these two dietary interventions and metabolic pathways on cancer cachexia is not fully understood. This dissertation investigates how metabolic adaptations in colorectal cancer alter glutamine and ketone metabolism to contribute to the progression of cancer cachexia. We particularly explore the role glutamine metabolism plays in cachexia induction. Specifically, we demonstrate a potential cachexia inducing mechanism mediated by glutamine deprecation and the over expression of FN14 (Fibroblast growth factor-inducible 14), a cachexia inducing protein. We found that, upon glutamine depletion, FN14 expression is mediated by hypermethylation of its promoter. We further find this newly identified regulator of FN14 aids in the progression of cachexia and the expression of FN14 can be reversed by alpha-ketoglutarate treatment. Finally, we exploit a novel model of cachexia that allows us to investigate the early metabolic changes within the tumor prior to the induction of cachexia. Our results indicate ketogenesis is occurring in colorectal cancer tumors and when applying a ketogenic diet to cancer types with increased tumor ketogenesis the induction of cachexia is exacerbated. These results further solidify the connection between tumor intrinsic metabolites and the exacerbation of cachexia further supporting the need for personalized dietary interventions in cachexia treatment based on tumor protein expression.