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Ataxin-10 is part of a cachexokine cocktail triggering cardiac metabolic dysfunction in cancer cachexia

Authors

  • M. Schaefer
  • C.U. Oeing
  • M. Rohm
  • E. Baysal-Temel
  • L.H. Lehmann
  • R. Bauer
  • H.C. Volz
  • M. Boutros
  • D. Sohn
  • C. Sticht
  • N. Gretz
  • K. Eichelbaum
  • T. Werner
  • M.N. Hirt
  • T. Eschenhagen
  • K. Mueller-Decker
  • O. Strobel
  • T. Hackert
  • J. Krijgsveld
  • H.A. Katus
  • M. Berriel Diaz
  • J. Backs
  • S. Herzig

Journal

  • Molecular Metabolism

Citation

  • Mol Metab 5 (2): 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.


DOI

doi:10.1016/j.molmet.2015.11.004