TY - JOUR
T1 - Ataxin-10 is part of a cachexokine cocktail triggering cardiac metabolic dysfunction in cancer cachexia
AU - Schäfer, Michaela
AU - Oeing, Christian U.
AU - Rohm, Maria
AU - Baysal-Temel, Ezgi
AU - Lehmann, Lorenz H.
AU - Bauer, Ralf
AU - Volz, H. Christian
AU - Boutros, Michael
AU - Sohn, Daniela
AU - Sticht, Carsten
AU - Gretz, Norbert
AU - Eichelbaum, Katrin
AU - Werner, Tessa
AU - Hirt, Marc N.
AU - Eschenhagen, Thomas
AU - Müller-Decker, Karin
AU - Strobel, Oliver
AU - Hackert, Thilo
AU - Krijgsveld, Jeroen
AU - Katus, Hugo A.
AU - Berriel Diaz, Mauricio
AU - Backs, Johannes
AU - Herzig, Stephan
N1 - Publisher Copyright:
© 2015 The Authors.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - 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.
AB - 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.
KW - Ataxin-10
KW - Cancer cachexia
KW - Cardiac dysfunction
KW - Fatty acid metabolism
UR - http://www.scopus.com/inward/record.url?scp=84958058862&partnerID=8YFLogxK
U2 - 10.1016/j.molmet.2015.11.004
DO - 10.1016/j.molmet.2015.11.004
M3 - Article
AN - SCOPUS:84958058862
SN - 2212-8778
VL - 5
SP - 67
EP - 78
JO - Molecular Metabolism
JF - Molecular Metabolism
IS - 2
ER -