Model of tumor–fat–muscle crosstalk in PDAC. Summary of the crosstalk between tumor, muscle, and fat in PDAC-associated cachexia. IL-6 produced by tumor epithelial cells acts to exacerbate both fat and muscle wasting, leading to myosteatosis and systemic inflammation as a result of increased lipolysis and production of IL-6 and FAs by fat. Production of IL6R by muscle is increased in the presence of PDAC and contributes to elevated sIL6R levels in plasma. Ultimately, the increases in both FAs and sIL6R in plasma act in a feed-forward mechanism, where muscle and fat contribute to each other’s wasting in PDAC cachexia.