PROJECT SUMMARY: PROJECT 1 Cancer cachexia, or progressive weight loss featuring immunodysmetabolism, causes ~1/3 of cancer deaths. Loss of muscle mass reduces performance status, predisposes to illness, and increases treatment toxicity while reducing efficacy. Not merely a feature of end-stage cancer, cachexia is a disease with specific, targetable mechanisms. Pre-clinical studies prove that targeting those mechanisms can preserve muscle and lengthen survival, with or without chemotherapy. Cachexia is especially devastating in pancreatic ductal adenocarcinoma (PDAC), afflicting 85% of PDAC patients, most of whom present with weight loss. There is no effective treatment for PDAC and 5-year survival is ~9%. Thus, until PDAC can be cured early in its course, we must manage cachexia, because preserving muscle mass and function will promote response to cancer treatment, improve quality of life, and increase survival. Overall, our Program team hypothesizes that PDAC tumor progression and cachexia is highly orchestrated by an IL-6/IL6R/STAT3/NF-B signaling axis. Project 2 will test NF-B in muscle inflammation and tumor progression, and Project 3 will study IL-6/STAT3/NF-B in tumor-stroma- immune interactions and the macroenvironment. Project 1 of this Program focuses on the crosstalk between adipose and skeletal muscle induced by PDAC tumors, and how IL6R, STAT3, and NF-B combine to produce fat and muscle loss in the PDAC macroenvironment. Abundant data demonstrate that weight loss in PDAC is primarily fat loss in PDAC. Moreover, we showed that fat loss is as predictive of mortality in PDAC as muscle loss, regardless of response to therapy, suggesting a central role for adipose wasting in cachexia. Now we demonstrate that tumor-induced, muscle-derived soluble IL6R appears to induce IL-6 mediated adipocyte lipolysis, products of which feed forward to induce myosteatosis, lipotoxicity, dysmetabolism, weakness and atrophy through a novel PKC-θ to PDK4 axis. Thus, we hypothesize that PDAC induces a feed-forward loop among tumor, fat, and muscle whereby tumor-induced IL-6 and other signals activate adipose STAT3 and lipolysis, products of which are taken up by muscle leading to myosteatosis, PKC-θ activation and subsequent myofiber STAT3, NF-B and PDK4 activation, which promote dysmetabolism, local inflammation and production of soluble IL6R to feed-forward activate adipose wasting. Blocking this cycle will preserve adipose and muscle wasting in PDAC. Using genetic mouse models, human specimens, advanced single cell resolution sequencing as well as correlative cachexia studies in a clinical trial, we will test our hypothesis in these specific aims: AIM 1. Interrogate the mechanisms of adipose-to-muscle crosstalk in the macroenvironment of PDAC cachexia. AIM 2. Interrogate mechanisms of muscle-to-adipose crosstalk in the macroenvironment of PDAC cachexia. AIM 3. Interrogate manifestations and mechanisms of the IL-6/IL6R/STAT3/NF-B pathway in patients with PDAC cachexia.

PROJECT NARRATIVE: PROJECT 1 Body weight loss in pancreatic cancer, recognized as progressive wasting of fat and muscle, is frequent and severe, reducing quality of life and response to therapy and increasing mortality. In partnership with the other Projects in this Program, we seek to understand how the tumor, fat and muscle communicate to each other within the body of an individual with pancreatic cancer. Using tissues from mouse models and from surgical pancreatic cancer patients, and blood samples and clinical data from an ongoing pancreatic cancer clinical trial, we will apply advanced analytical techniques including at the single cell level to identify new molecular targets to improve treatment and quality of life in patients with pancreatic cancer.