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

ABSTRACT: 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

SUBMITTER: Rupert JE 

PROVIDER: S-EPMC8185651 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature