Molecular Metabolism (Feb 2016)
Ataxin-10 is part of a cachexokine cocktail triggering cardiac metabolic dysfunction in cancer cachexia
- Michaela Schäfer,
- Christian U. Oeing,
- Maria Rohm,
- Ezgi Baysal-Temel,
- Lorenz H. Lehmann,
- Ralf Bauer,
- H. Christian Volz,
- Michael Boutros,
- Daniela Sohn,
- Carsten Sticht,
- Norbert Gretz,
- Katrin Eichelbaum,
- Tessa Werner,
- Marc N. Hirt,
- Thomas Eschenhagen,
- Karin Müller-Decker,
- Oliver Strobel,
- Thilo Hackert,
- Jeroen Krijgsveld,
- Hugo A. Katus,
- Mauricio Berriel Diaz,
- Johannes Backs,
- Stephan Herzig
Affiliations
- Michaela Schäfer
- Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, 85764 Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
- Christian U. Oeing
- Department of Cardiology, Angiology and Pulmonology, University Hospital Heidelberg, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany; Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, 69120 Heidelberg, Germany
- Maria Rohm
- Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, 85764 Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, 69120 Heidelberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
- Ezgi Baysal-Temel
- Department of Cardiology, Angiology and Pulmonology, University Hospital Heidelberg, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany; Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, 69120 Heidelberg, Germany
- Lorenz H. Lehmann
- Department of Cardiology, Angiology and Pulmonology, University Hospital Heidelberg, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany; Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, 69120 Heidelberg, Germany
- Ralf Bauer
- Department of Cardiology, Angiology and Pulmonology, University Hospital Heidelberg, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany
- H. Christian Volz
- Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany
- Michael Boutros
- Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany
- Daniela Sohn
- Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, 85764 Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, 69120 Heidelberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
- Carsten Sticht
- Center for Medical Research, University of Mannheim, 68167 Mannheim, Germany
- Norbert Gretz
- Center for Medical Research, University of Mannheim, 68167 Mannheim, Germany
- Katrin Eichelbaum
- Department for Cell Signaling and Mass Spectrometry, Max Delbrück Center, 13092 Berlin, Germany
- Tessa Werner
- Department of Experimental and Clinical Pharmacology and Toxicology, University Medical Center, 20246 Hamburg-Eppendorf, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Hamburg/Kiel/Lübeck, 20246 Hamburg-Eppendorf, Germany
- Marc N. Hirt
- Department of Experimental and Clinical Pharmacology and Toxicology, University Medical Center, 20246 Hamburg-Eppendorf, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Hamburg/Kiel/Lübeck, 20246 Hamburg-Eppendorf, Germany
- Thomas Eschenhagen
- Department of Experimental and Clinical Pharmacology and Toxicology, University Medical Center, 20246 Hamburg-Eppendorf, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Hamburg/Kiel/Lübeck, 20246 Hamburg-Eppendorf, Germany
- Karin Müller-Decker
- Core Facility Tumor Models, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Oliver Strobel
- Department of General Surgery, University of Heidelberg, 69120 Heidelberg, Germany
- Thilo Hackert
- Department of General Surgery, University of Heidelberg, 69120 Heidelberg, Germany
- Jeroen Krijgsveld
- Genome Biology Unit, EMBL, 69117 Heidelberg, Germany
- Hugo A. Katus
- Department of Cardiology, Angiology and Pulmonology, University Hospital Heidelberg, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany
- Mauricio Berriel Diaz
- Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, 85764 Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, 69120 Heidelberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
- Johannes Backs
- Department of Cardiology, Angiology and Pulmonology, University Hospital Heidelberg, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany; Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, 69120 Heidelberg, Germany; Corresponding author. Department of Cardiology, Angiology and Pulmonology, University Hospital Heidelberg, 69120 Heidelberg, Germany. Tel.: +49 6221 5637714; fax: +49 6221 565573.
- Stephan Herzig
- Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, 85764 Neuherberg, Germany; Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Corresponding author. Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, 85764 Neuherberg, Germany. Tel.: +49 (0)89 3187 1046.
- Journal volume & issue
-
Vol. 5,
no. 2
pp. 67 – 78
Abstract
Objectives: Cancer cachexia affects the majority of tumor patients and significantly contributes to high mortality rates in these subjects. Despite its clinical importance, the identity of tumor-borne signals and their impact on specific peripheral organ systems, particularly the heart, remain mostly unknown. Methods and results: By combining differential colon cancer cell secretome profiling with large-scale cardiomyocyte phenotyping, we identified a signature panel of seven “cachexokines”, including Bridging integrator 1, Syntaxin 7, Multiple inositol-polyphosphate phosphatase 1, Glucosidase alpha acid, Chemokine ligand 2, Adamts like 4, and Ataxin-10, which were both sufficient and necessary to trigger cardiac atrophy and aberrant fatty acid metabolism in cardiomyocytes. As a prototypical example, engineered secretion of Ataxin-10 from non-cachexia-inducing cells was sufficient to induce cachexia phenotypes in cardiomyocytes, correlating with elevated Ataxin-10 serum levels in murine and human cancer cachexia models. Conclusions: As Ataxin-10 serum levels were also found to be elevated in human cachectic cancer patients, the identification of Ataxin-10 as part of a cachexokine cocktail now provides a rational approach towards personalized predictive, diagnostic and therapeutic measures in cancer cachexia. Author Video: Author Video Watch what authors say about their articles Keywords: Cancer cachexia, Ataxin-10, Cardiac dysfunction, Fatty acid metabolism