Metabolic vulnerability due to dysregulated lipid metabolism in PDAC cachexia

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PROJECT SUMMARY Cachexia is a devastating complication of cancers and other inflammatory conditions that is defined by rapid and persistent loss of fat and muscle that is not reversed by caloric supplementation. Cachexia is a major determinant of both lifespan and quality of life that compromises the ability of patients to recover from life- saving or extending interventions. Although descriptions of cachexia go back as far as Hippocrates, the mechanisms underlying this catabolic state are poorly understood, and there remain no effective treatments. Over 80% of patients with pancreatic ductal adenocarcinoma (PDAC) suffer from cachexia at some point during their cancer journey, adding significant morbidity and mortality to an already dire disease. We have recently found that PDAC alters the ability of the body to utilize fat stores as fuels. The ability of an organism to survive metabolic challenges, including low nutrition or infection, is dependent upon accessing energy stored in fat and oxidizing it in the liver. In this proposal we will investigate the role of this altered lipid metabolism in PDAC-associated cachexia and examine the relationship between adipose tissue, the liver, and skeletal muscle preservation. The significance of this proposal resides in its use of genetic and metabolomic tools and a unique patient tissue resource to investigate an unexplored area of the cancer macroenvironment with new collaborations and efforts directed at isolating and defining the interorgan processes that enable resilience to physiologic threats. The long-term goal of our research is to gain a mechanistic understanding of how lipid metabolism impacts skeletal muscle homeostasis in normal physiology and how this is modified in cancer cachexia in order to develop more effective therapeutic approaches.