Rupert, Joseph E.Narasimhan, AshokJengelley, Daenique H.A.Jiang, YanlinLiu, JianguoAu, ErnieSilverman, Libbie M.Sandusky, GeorgeBonetto, AndreaCao, ShaLu, XiaoyuO’Connell, Thomas M.Liu, YunlongKoniaris, Leonidas G.Zimmers, Teresa A.2022-12-152022-12-152021-06-07Rupert JE, Narasimhan A, Jengelley DHA, et al. Tumor-derived IL-6 and trans-signaling among tumor, fat, and muscle mediate pancreatic cancer cachexia. J Exp Med. 2021;218(6):e20190450. doi:10.1084/jem.20190450https://hdl.handle.net/1805/30755Most patients with pancreatic adenocarcinoma (PDAC) suffer cachexia; some do not. To model heterogeneity, we used patient-derived orthotopic xenografts. These phenocopied donor weight loss. Furthermore, muscle wasting correlated with mortality and murine IL-6, and human IL-6 associated with the greatest murine cachexia. In cell culture and mice, PDAC cells elicited adipocyte IL-6 expression and IL-6 plus IL-6 receptor (IL6R) in myocytes and blood. PDAC induced adipocyte lipolysis and muscle steatosis, dysmetabolism, and wasting. Depletion of IL-6 from malignant cells halved adipose wasting and abolished myosteatosis, dysmetabolism, and atrophy. In culture, adipocyte lipolysis required soluble (s)IL6R, while IL-6, sIL6R, or palmitate induced myotube atrophy. PDAC cells activated adipocytes to induce myotube wasting and activated myotubes to induce adipocyte lipolysis. Thus, PDAC cachexia results from tissue crosstalk via a feed-forward, IL-6 trans-signaling loop. Malignant cells signal via IL-6 to muscle and fat, muscle to fat via sIL6R, and fat to muscle via lipids and IL-6, all targetable mechanisms for treatment of cachexia.en-USAttribution 4.0 InternationalAdenocarcinomaAdipose tissueCachexiaSkeletal muscle fibersPancreatic neoplasmsArticle