PROJECT SUMMARY: PROJECT 2 Cachexia is a debilitating syndrome that results in severe, involuntary weight loss due to the depletion of skeletal muscle and adipose tissues. This syndrome occurs in a majority of cancers and contributes to approximately a third of all cancer deaths. Currently, no effective therapy exists to combat this malignant disorder. For pancreatic ductal adenocarcinoma (PDAC), the most aggressive formof pancreatic cancer, the potential benefit for effective cachexia therapies may be even greater than for other cachexia-associated malignancies, since 85% of these patients lose on average 14% of their pre-illness weight, and cachexia dramatically limits their ability to tolerate surgery, chemo- or radiotherapy. New therapies will likely evolve from an enhanced understanding of the mechanisms leading to muscle wasting and tumor development (the primary driver of cachexia). This program project brings together expert investigators in skeletal muscle, oncology, immunology, and cachexia, to explore the role an NF-B/IL-6/STAT3 signaling axis within the macroenvironment of cancer cachexia – considering both mechanisms of muscle loss and the development of PDAC. In Project 2 of this program, focus will be placed on the NF-B portion of this signaling axis. Recent efforts have centered on two new concepts. The first is that cancer cachexia associates with the activation of muscle stem cells initiating a repair pr ocess on the muscle fiber. NF-B is activated in stem cells, and functions to block repair and promote muscle wasting through the regulation of a local muscle inflammatory condition. The second discovery provides insight in how NF-B functions within the tumor cell during development of PDAC. Using a mouse model of pancreatic cancer, we showed that NF-B plays a critical role in protecting tumor cells from the surveillance property of anti-tumor macrophages and cytotoxic T cells. NF-B is able to suppress both innate and adaptive immunity through the regulation of the immunosuppressive cytokine, GDF15. The goal of this project is to explore the hypothesis that NF-B functions in the macroenvironment of cancer cachexia by acting in muscle stem cells to block muscle repair, as well as promoting PDAC through the production of immunosuppressive genes such as GDF-15. Towards this goal we seek to perform the following two specific aims: 1) Determine the relevance of NF-B regulation of muscle inflammation in cancer cachexia; and 2) Determine how NF-B regulation of GDF-15 and immune modulation promotes PDAC. Achieving this goal will enhance our understanding of the relevance of NF- B and how this signaling component intersects with IL-6 and STAT3 to regulate muscle wasting and tumor development within the macroenvironment of cancer cachexia.