Tumor-derived IL-6 and trans-signaling among tumor, fat, and muscle mediate pancreatic cancer cachexia

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 grea...

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Published in:The Journal of experimental medicine Vol. 218; no. 6
Main Authors: Rupert, Joseph E, Narasimhan, Ashok, Jengelley, Daenique H A, Jiang, Yanlin, Liu, Jianguo, Au, Ernie, Silverman, Libbie M, Sandusky, George, Bonetto, Andrea, Cao, Sha, Lu, Xiaoyu, O'Connell, Thomas M, Liu, Yunlong, Koniaris, Leonidas G, Zimmers, Teresa A
Format: Journal Article
Language:English
Published: United States 07.06.2021
Subjects:
3T3 Cells
Adenocarcinoma - metabolism
Adenocarcinoma - pathology
Adipocytes - metabolism
Adipose Tissue - metabolism
Adipose Tissue - pathology
Aged
Aged, 80 and over
Animals
Cachexia - metabolism
Cachexia - pathology
Cell Line
Cell Line, Tumor
Disease Models, Animal
Female
Humans
Interleukin-6 - metabolism
Lipolysis - physiology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle Fibers, Skeletal - metabolism
Muscle Fibers, Skeletal - pathology
Muscle, Skeletal - metabolism
Muscle, Skeletal - pathology
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Signal Transduction - physiology
ISSN:1540-9538, 1540-9538
Online Access:Get more information
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Summary: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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ISSN:1540-9538
1540-9538
DOI:10.1084/jem.20190450