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


Schafer, M., Oeing, C. U., Rohm, M., Baysal-Temel, E., Lehmann, L. H., Bauer, R., Volz, H. C., Boutros, M., Sohn, D., Sticht, C., Gretz, N., Eichelbaum, K., Werner, T., Hirt, M. N., Eschenhagen, T., Muller-Decker, K., Strobel, O., Hackert, T., Krijgsveld, J., Katus, H. A., Berriel Diaz, M., Backs, J., and Herzig, S. (2016). Mol Metab 5, 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.