Elucidating the role of hepatic ketogenesis in pancreatic cancer cachexia and recovery - PROJECT SUMMARY/ABSTRACT 80% of patients with Pancreatic Ductal Adenocarcinoma (PDAC) develop cachexia, which results in dispropor- tionate skeletal muscle mass loss, relative to caloric deficits. Cachexia causes functional impairment and ineli- gibility for anti-tumor therapeutic interventions, leading to drastically lower patient quality of life and increased mortality. Supplemental nutrition is not sufficient to prevent tissue loss, and there is an abject lack of targeted anti-cachectic therapeutics. This is largely due to an incomplete understanding of how effectors, such as inter- leukin 6 (IL-6), drive cachexia, and mechanistic studies that poorly reflect the clinical scenarios of PDAC survi- vorship. Improving the quality of life and survivorship of patients with PDAC requires that we address a funda- mental knowledge gap in the mechanisms of cachexia persistence after cancer recovery. Our recent work shows that systemic inflammation in PDAC prevents the liver from adapting to ketogenic metabolism during nutritional scarcity, which leads to muscle loss. Loss of hepatic signal transducer and activator of transcription 3 (STAT3) is sufficient to restore ketogenic potential and prevent muscle loss in PDAC mice. This work is the first to show that improving hepatic fatty acid oxidation prevents cachexia progression. To improve the translation of these findings we must address two unmet needs: 1) the mechanism of STAT3-driven down regulation of lipid oxidation and 2) studies that address cachexia recovery in cancer survivors. Based on our prior work, we hypothesize that STAT3 signaling acts on the liver to induce metabolic changes that persist after cancer recovery, at the detriment of the muscle. This project is innovative because it uses advanced epigenetic techniques combined with a novel mouse model of PDAC survivorship to clearly define the epigenetic reprogramming events that persist after tumor clearance and increase vulnerability of muscle to nutritional stress. The significance of this project lies in pre-clinical testing of metabolic interventions to protect muscle during PDAC recovery, defining a previously undescribed action of STAT3 in hepatic metabolism control, and linking long-term metabolic dysfunction to epi- genetic reprogramming during PDAC cachexia. The long-term goal of our research is to improve the quality of life, from diagnosis through survivorship, of patients with cancer cachexia through a mechanistic understanding of inter-organ metabolic events.
