PROJECT SUMMARY: PROJECT 3 PDAC is among the most deadly malignant solid tumors, with approximately 92% of patients succumbing to the disease within five years of diagnosis, and with no effective therapies beyond surgery. Importantly, it is widely recognized that patients with PDAC are especially prone to cachexia, a syndrome characterized by pronounced weight loss due to depleting skeletal muscle and adipose tissues. As a result, patients are often weak and fatigued, which makes them less tolerant to chemo- and radiotherapy. The histopathological hallmark of PDAC is its uniquely dense stromal reaction, comprised of activated, cancer associated fibroblasts, increased extra- cellular matrix (ECM), immune cell infiltrates, and abnormal angiogenesis. This has engendered attention for selectively targeting the tumor stroma to increase therapeutic efficacy. However, stromal cancer-associated fibroblasts can also have tumor suppressive functions, challenging the efficacy of stromal-targeting therapies. In addition, there is increasing appreciation for the dual role of stromal mesenchymal cells in muscle homeostasis and regeneration, as well as in muscle wasting diseases, including cancer cachexia. Progress in tackling PDAC will require new knowledge of its macroenvironment encompassing crosstalk between the tumor and peripheral tissues. In Project 3, we posit the IL6/STAT3 pathway is a key pathway involved in PDAC macroenvironment cross-talk. Synergistic interactions with the Projects and Cores in this Program Project will allow us to test the hypothesis that STAT3 signaling in stromal mesenchymal cells present in the tumor and muscle is a component of a feed-forward loop in the tumor macroenvironment that favors PDAC progression and cancer cachexia.