Rupert, Joseph E.Bonetto, AndreaNarasimhan, AshokLiu, YunlongO’Connell, Thomas M.Koniaris, Leonidas G.Zimmers, Teresa A.2022-05-092022-05-092020-09-17Rupert, J. E., Bonetto, A., Narasimhan, A., Liu, Y., O’Connell, T. M., Koniaris, L. G., & Zimmers, T. A. (2020). IL-6 Trans-Signaling and Crosstalk Among Tumor, Muscle and Fat Mediate Pancreatic Cancer Cachexia (p. 2020.09.16.300798). https://doi.org/10.1101/2020.09.16.300798https://hdl.handle.net/1805/28870Most patients with pancreatic adenocarcinoma (PDAC) suffer unintentional weight loss, or cachexia. Interleukin-6 causes cachexia in mice and associates with mortality in PDAC. Here we show that tumor cell-derived IL-6 mediates crosstalk between tumor and peripheral tissues to promote cachexia. Tumor-cell IL-6 elicits expression of IL-6 in fat and IL-6 and IL-6 receptor (IL6R) in muscle, concomitantly raising both in blood. Inflammation-induced adipose lipolysis elevates circulating fatty acids, which cooperate with IL-6 to induce skeletal muscle dysmetabolism and wasting. Thus, PDAC induces crosstalk among tumor, fat and muscle via a feed-forward, IL-6 signaling loop. Tumor talks to muscle and fat through IL-6, and muscle to fat via IL6R trans-signaling, and fat to muscle through lipids and fatty acids. Disruption of this crosstalk by depletion of tumor-derived IL-6 halved fat wasting and abolished muscle loss, supporting IL-6, IL-6R and lipids as causal nodes for tissue crosstalk in PDAC cachexia. Significance PDAC-associated cachexia significantly increases patient morbidity and mortality. This study identifies muscle and fat crosstalk via IL6R trans-signaling in concert with muscle steatosis as a main driver of PDAC-associated cachexia.enPublisher PolicyPancreatic CancerCachexiaTumorArticle