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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| Veröffentlicht in: | The Journal of experimental medicine Jg. 218; H. 6 |
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| 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 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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| AbstractList | 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.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. 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. |
| Author | Bonetto, Andrea Liu, Jianguo O'Connell, Thomas M Narasimhan, Ashok Sandusky, George Au, Ernie Koniaris, Leonidas G Rupert, Joseph E Liu, Yunlong Silverman, Libbie M Cao, Sha Lu, Xiaoyu Jengelley, Daenique H A Jiang, Yanlin Zimmers, Teresa A |
| Author_xml | – sequence: 1 givenname: Joseph E surname: Rupert fullname: Rupert, Joseph E organization: Department of Biochemistry, Indiana University School of Medicine, Indianapolis, IN – sequence: 2 givenname: Ashok surname: Narasimhan fullname: Narasimhan, Ashok organization: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN – sequence: 3 givenname: Daenique H A surname: Jengelley fullname: Jengelley, Daenique H A organization: Department of Biochemistry, Indiana University School of Medicine, Indianapolis, IN – sequence: 4 givenname: Yanlin surname: Jiang fullname: Jiang, Yanlin organization: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN – sequence: 5 givenname: Jianguo surname: Liu fullname: Liu, Jianguo organization: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN – sequence: 6 givenname: Ernie surname: Au fullname: Au, Ernie organization: Department of Biochemistry, Indiana University School of Medicine, Indianapolis, IN – sequence: 7 givenname: Libbie M surname: Silverman fullname: Silverman, Libbie M organization: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN – sequence: 8 givenname: George surname: Sandusky fullname: Sandusky, George organization: Department of Pathology, Indiana University School of Medicine, Indianapolis, IN – sequence: 9 givenname: Andrea surname: Bonetto fullname: Bonetto, Andrea organization: Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN – sequence: 10 givenname: Sha surname: Cao fullname: Cao, Sha organization: Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN – sequence: 11 givenname: Xiaoyu surname: Lu fullname: Lu, Xiaoyu organization: Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN – sequence: 12 givenname: Thomas M surname: O'Connell fullname: O'Connell, Thomas M organization: Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN – sequence: 13 givenname: Yunlong surname: Liu fullname: Liu, Yunlong organization: Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN – sequence: 14 givenname: Leonidas G surname: Koniaris fullname: Koniaris, Leonidas G organization: Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN – sequence: 15 givenname: Teresa A surname: Zimmers fullname: Zimmers, Teresa A organization: Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33851955$$D View this record in MEDLINE/PubMed |
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| Snippet | Most patients with pancreatic adenocarcinoma (PDAC) suffer cachexia; some do not. To model heterogeneity, we used patient-derived orthotopic xenografts. These... |
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| SubjectTerms | 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 |
| Title | Tumor-derived IL-6 and trans-signaling among tumor, fat, and muscle mediate pancreatic cancer cachexia |
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