Microbiome-Mitochondrial Interactions Driving Cancer-Induced Cachexia in the Obese State - PROJECT SUMMARY Research: At the time of cancer diagnosis, 40% - 60% of patients are overweight or obese. Despite this, there is a dearth of literature on the impact of weight status on cancer-induced cachexia - the unintentional loss of lean mass, which directly contributes to functional dependency, poor treatment outcomes, and decreased survival. An “obesity paradox” has been postulated; however, the epidemiology remains equivocal on the benefits/detriments of obesity on cachexia status. While obesity and cachexia are diseases at opposite ends of the weight spectrum, these pathologies share some underlying perturbations (e.g. mitochondrial dysfunction and microbial dysbiosis) that may exacerbate functional decrements when these morbidities co-occur. Evidence supports a role for mitochondrial dysfunction in the progression of cachexia. Indeed, we and others have shown that impaired mitochondrial function and dysregulated mitochondrial quality control (biogenesis, dynamics, and mitophagy) are associated with cachexia. Further, evidence links specific metabolites, microbes, and their metabolic pathways with cachexia status. Incidentally, obesity is also associated with mitochondrial dysfunction and alterations in gut bacterial populations. However, the impact of obesity on cachexia and associated perturbations (mitochondrial dysfunction and gut dysbiosis) has not been established. Therefore, the goal of my F99/K00 is to 1) understand the microbial and metabolic perturbations associated with cancer cachexia in the obese state (F99), and 2) using multi-omics, examine the relationship between microbes and mitochondria in cancer cachexia and identify strategies for intervention. My central hypothesis is that cancer-induced cachexia is exacerbated in an obese state and gut microbial-muscle mitochondria interactions are central in the coordination of this worsened phenotype. I will test this hypothesis in two specific aims as follows: 1) Examine the impact of obesity on microbial alterations, metabolic perturbations, and skeletal muscle dysfunction with cancer-induced cachexia in the obese state and 2) Establish microbiome-mitochondria interactions in cancer cachexia in the context of obesity and identify strategies for intervention. These studies will uncover the impact of obesity on cancer cachexia and will identify microbiome-mitochondrial interactions, provoking novel opportunities for intervention. Career Goals: My long-term research goal is to become an independent researcher at a top-tier research institution focused on prevention/treatment of cancer and cancer therapy related off-target effects including cachexia. Career Development Plan: The proposed career development plan is designed to enhance my knowledge, technical expertise, and professional skills. Specifically, I will receive training in 1) obesity phenotyping and cachexia modeling, 2) mitochondrial behavior, 3) microbiome and microbial metabolites, and 4) professional development. The proposed F99/K00 award is an important step in realizing my career goal. This proposed research and training in this F99/K00 will provide me with the acumen to launch a successful independent career in the field of cancer cachexia.
