PROJECT SUMMARY Cachexia is a devastating complication of pancreatic ductal adenocarcinoma (PDAC) defined by loss of lean mass out of proportion to the caloric deficit. Cachexia is a major determinant of both lifespan and quality of life in patients with PDAC. The mechanisms underlying this catabolic state are poorly understood, and there remain no effective treatments. We have recently found that PDAC alters the regulation of metabolic genes in the liver, the organ that controls whole-body physiology in response to nutrient availability. The metabolic program reflects high energy availability in the livers of cachectic mice, suggesting a mismatch between hepatic nutrient sensing and availability. In this proposal we will investigate the role of this hepatic metabolic reprogramming on PDAC-associated cachexia. In Aim 1 we will modulate the hepatic activity of mTOR, a nutrient-sensing kinase that controls liver metabolism, to demonstrate that modification of hepatic nutrient sensing impacts tissue wasting. In Aim 2 we will investigate the effect of PDAC on nutritive and circadian regulation of liver metabolism and explore human samples for coherent effects. These Aims will provide fundamental insight into the deregulation of hepatic metabolism by PDAC, its role in cancer cachexia, and the circulating signals that mediate these changes. My goal is to become a successful independent physician-scientist investigator and a leader in the field of cancer metabolism, with the long-term goals of identifying new therapeutic targets to improve lifespan and quality of life in cancer patients. During this mentored career development award, I will receive excellent mentorship from Dr. Rosalie Sears, a leader in pancreatic tumor biology and Director of the Brenden-Colson Center for Pancreatic Care. I will undertake additional training in the field of hepatic metabolism, with guidance from Dr. Markus Grompe, and cachexia physiology, under the tutelage of Dr. Daniel Marks.