Progressive weight loss also known as cancer cachexia, afflicts ~85% of patients with pancreatic ductal adenocarcinoma (PDAC). Cachexia associates with treatment toxicity, morbidity, and mortality, contributing to the 91% 5-year mortality among patients with PDAC. Moreover, while most patients with PDAC die with cachexia, we posit that many or most die of cachexia. Currently there are no approved treatments for cachexia, although pre-clinical studies demonstrate that preserving fat and muscle can prolong function and life with and without chemotherapy. Here we show a novel pathway linking tumor, adipose, and muscle. We show that PDAC tumors express Interleukin-6 (IL-6), which circulates to fat, causing local inflammation and further secretion of IL-6. IL-6 also circulates to muscle, inducing feed-forward production of IL-6 and shedding of the IL-6 receptor (sIL6R). Muscle-derived IL6R circulates to fat, initiating trans-signaling and adipocyte lipolysis. Products of lipolysis are taken up by skeletal muscle, leading to myosteatosis, lipotoxic stress, and muscle atrophy. Inhibition of tumor IL-6 reduces adipose wasting and prevents muscle loss, demonstrating a key role for IL-6 in the PDAC macro-environment. Preliminary data from patients shows IL-6 expression in tumors, identifies IL-6 as an upstream regulator in blood, demonstrates IL-6 and IL-6R in adipose tissue, and documents a STAT3/NF-kB gene signature in muscle. However, only a subset of patients showed elevated IL- 6 pathway activation, whereas 85% of patients experience cachexia. This suggests that IL-6-induced inflammation might be a driver in a subset of patients, potentially linked to tumor production of IL-6. Indeed, our preliminary data using orthotopic xenografts of human tumors in mice indicates that patient tumors have differing intrinsic abilities to cause cachexia, which might be related to IL-6 expression from the tumor. Here we will interrogate human tissue specimens to document the diversity in the cachexia phenotype and to identify patients with IL-6 pathway activity. As well, we will as use patient-derived orthotopic xenografts in mouse models to evaluate the intrinsic ability of tumors to cause cachexia and the therapeutic potential of blocking IL- 6 trans-signaling and tissue crosstalk. To do so we will leverage our existing cachexia biorepository and our lines of PDAC cachexia “avatars”—mice implanted with human tumor fragments. AIM 1: Interrogate phenotypic and molecular heterogeneity and tumor-tissue crosstalk in biospecimens from patients with well characterized body composition and pancreatic cancer cachexia. AIM 2: Evaluate functional heterogeneity in the capacity of individual tumors to cause cachexia AIM 3: Test the importance of tumor-tissue crosstalk via IL-6 trans-signaling and lipolysis in a pre-clinical mouse hospital setting.