TY - JOUR
T1 - Tumor-derived IL-6 and trans-signaling among tumor, fat, and muscle mediate pancreatic cancer cachexia
AU - Rupert, Joseph E.
AU - Narasimhan, Ashok
AU - Jengelley, Daenique H.A.
AU - Jiang, Yanlin
AU - Liu, Jianguo
AU - Au, Ernie
AU - Silverman, Libbie M.
AU - Sandusky, George
AU - Bonetto, Andrea
AU - Cao, Sha
AU - Lu, Xiaoyu
AU - O’Connell, Thomas M.
AU - Liu, Yunlong
AU - Koniaris, Leonidas G.
AU - Zimmers, Teresa A.
N1 - Publisher Copyright:
© 2021 Rupert et al.
PY - 2021/4/14
Y1 - 2021/4/14
N2 - Most 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.
AB - Most 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.
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U2 - 10.1084/jem.20190450
DO - 10.1084/jem.20190450
M3 - Article
C2 - 33851955
AN - SCOPUS:85104235893
SN - 0022-1007
VL - 218
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 6
M1 - e20190450
ER -