Intercellular Communication in Cancer Cachexia: Impact of Obesity and Exercise - Research: At the time of cancer diagnosis, 40%–60% of patients are overweight or obese. Despite this, there is a lack in understanding how pre-existing obesity influences the development and severity of cancer cachexia— a multifactorial wasting syndrome characterized by the unintentional loss of lean mass, which contributes to poor physical function, treatment intolerance, and reduced survival. While an “obesity paradox” has been proposed, suggesting higher body mass may be protective, emerging data from my F31 and F99 demonstrates obesity is not protective against cachexia, exacerbates muscle metabolic dysfunction, and impairs mitochondrial quality control with cancer. Both obesity and cachexia independently feature mitochondrial dysfunction and systemic inflammation, and when they co-occur, these perturbations may worsen muscle dysfunction and metabolic decline. Extracellular vesicles (EVs) have emerged as critical mediators of cancer-host communication and are known to be altered by both cancer and obesity. Recent evidence suggests tumor- and tissue-derived EVs contribute to skeletal muscle dysfunction through delivery of inflammatory mediators, lipids, and regulatory RNAs that impair mitochondrial health. Notably, exercise is a potent modulator of EV secretion and cargo composition and may represent a non-pharmacological strategy to mitigate EV-driven muscle impairments in cancer survivors with obesity. The goal of my K00 is to develop a mechanistic understanding of the overlap between obesity and cancer cachexia so future studies can develop effective countermeasures. My central hypothesis is that EVs drive cancer induced skeletal muscle wasting and dysfunction in the obese state, and that exercise modifies EV signaling to counteract these effects. I will test this hypothesis through two specific aims: 1) Define EV-mediated mechanisms linking cancer and obesity to cachexia-induced muscle dysfunction, and 2) Establish the therapeutic potential of exercise to improve quality of life through EV-mediated mechanisms in cancer survivors with obesity. This work will generate mechanistic insight into how EVs contribute to cancer-induced muscle dysfunction in the context of obesity and will identify exercise-responsive EVs as potential biomarkers or therapeutic targets for intervention. Career Goals: My long-term goal is to become an independent, NCI-funded investigator at a leading research institution, focused on understanding and treating cancer-associated muscle dysfunction, with a particular emphasis on obesity and survivorship outcomes. Career Development Plan: This K00 award will provide comprehensive training in EV biology, exercise oncology, and metabolism, complementing my prior expertise in cancer biology, skeletal muscle, and obesity. Specifically, I will receive training in 1) bioinformatics, 2) EV biology, 3) translational research, and 4) professional development. The proposed K00 will equip me with technical and conceptual skills needed to launch a successful independent research career and improve outcomes for cancer patients affected by obesity and cachexia.
