Browsing by Author "Au, Ernie"

Now showing 1 - 1 of 1
  • Thumbnail Image
    Item
    Tumor-derived IL-6 and trans-signaling among tumor, fat, and muscle mediate pancreatic cancer cachexia
    (Rockefeller University Press, 2021-06-07) 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.; Surgery, School of Medicine
    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.