Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 218, Issue 6, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20190450
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Funding
- National Institutes of Health [R01CA122596, R01CA194593, R01GM137656, R21CA190028]
- U.S. Department of Veterans Affairs [I01BX004177, I01CX002046]
- Indiana University Simon Comprehensive Cancer Center
- Lustgarten Foundation
- Lilly Endowment, Inc.
- Purdue University Center for Cancer Research [P30CA023168]
- Walther Cancer Foundation
- Indiana University Simon Comprehensive Cancer Center [P30CA082709]
- National Institutes of Health training grant [T32HL007910]
- Indiana University
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The study revealed that most patients with pancreatic adenocarcinoma suffer from cachexia, which is mainly due to tissue crosstalk mediated via IL-6 signaling affecting muscle and adipocytes, providing targetable mechanisms for cachexia treatment.
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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