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Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle

Nature Medicine volume 24, pages 770–781 (2018)Cite this article

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Abstract

Patients with metastatic cancer experience a severe loss of skeletal muscle mass and function known as cachexia. Cachexia is associated with poor prognosis and accelerated death in patients with cancer, yet its underlying mechanisms remain poorly understood. Here, we identify the metal-ion transporter ZRT- and IRT-like protein 14 (ZIP14) as a critical mediator of cancer-induced cachexia. ZIP14 is upregulated in cachectic muscles of mice and in patients with metastatic cancer and can be induced by TNF-α and TGF-β cytokines. Strikingly, germline ablation or muscle-specific depletion of Zip14 markedly reduces muscle atrophy in metastatic cancer models. We find that ZIP14-mediated zinc uptake in muscle progenitor cells represses the expression of MyoD and Mef2c and blocks muscle-cell differentiation. Importantly, ZIP14-mediated zinc accumulation in differentiated muscle cells induces myosin heavy chain loss. These results highlight a previously unrecognized role for altered zinc homeostasis in metastatic cancer–induced muscle wasting and implicate ZIP14 as a therapeutic target for its treatment.

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Fig. 1: Characterization of metastatic cancer–induced cachexia models.
Fig. 2: The metal-ion transporter gene Zip14 is upregulated in cachectic muscles from both 4T1 and C26m2 metastatic mouse models.
Fig. 3: ZIP14 is upregulated in cachectic muscles from metastatic mouse models and patients, and its expression is induced by TNF-α and TGF-β.
Fig. 4: ZIP14-mediated zinc uptake in muscles promotes metastatic cancer–induced cachexia.
Fig. 5: ZIP14-mediated zinc accumulation blocks muscle-cell differentiation and induces myosin heavy chain loss.

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Acknowledgements

We would like to thank A. Ferrando (Columbia University Medical Center, CUMC), G. Karsenty (CUMC), T. Oskarsson (Deutsches Krebsforschungszentrum/German Cancer Center), D. Guttridge (Ohio State University), U. Klein (Leeds, UK) and members of the Acharyya laboratory for helpful insights throughout the study. We thank J. Massagué (Memorial Sloan Kettering Cancer Center), J. Sage (Stanford University) and Y. Kang (Princeton University) for sharing cell lines. We would like to thank K. Macrenaris and R. Sponenburg from Northwestern University Quantitative Bio-element Imaging Center (QBIC), supported by NASA Ames Research Center NNA06CB93G, and Y. Zhang and K. Schey from Vanderbilt University Imaging Mass Spectrometry Center for invaluable help with single-fiber mass spectrometry analyses. We would like to thank L. Munoz and T. Waddell from the Department of Pathology and Cell Biology at New York Presbyterian Hospital Center for muscle collection during autopsies. University of Nebraska Medical Center Rapid Autopsy Program was supported by National Institutes of Health (NIH) P50CA127297, U01CA210240 and 5R50CA211462 (to P.M.G. and M.A.H.). Establishment of the congenic Balb/c Zip14-knockout mice was supported by DK080706 (to M.D.K.). Establishment of lung cancer models was supported by National Cancer Institute R00CA172697 (to S.A.). This work was supported by Institutional start-up funds from CUIMC to S.A. and by Herbert Irving Comprehensive Cancer Center’s 5P30CA013696-43 Cancer Center Support Grant-Inter-Programmatic Pilot Project to S.A. Schematic models were generated in part using Servier Medical Art, licensed under a Creative Commons Attribution (CC BY) 3.0 License, with further modifications in some cases.

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  1. These authors contributed equally: Gang Wang, Anup K. Biswas, Wanchao Ma.

Authors and Affiliations

  1. Institute for Cancer Genetics, Columbia University, New York, NY, USA

    Gang Wang, Anup K. Biswas, Wanchao Ma, Courtney Coker & Swarnali Acharyya

  2. Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Manoj Kandpal & Ramana V. Davuluri

  3. Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA

    Paul M. Grandgenett & Michael A. Hollingsworth

  4. Department of Structural & Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Rinku Jain

  5. Division of Neuropathology, Department of Pathology and Cell Biology, Columbia University Irving Medical Center and New York Presbyterian Hospital, New York, NY, USA

    Kurenai Tanji

  6. Mailman School of Public Health, Columbia University, New York, NY, USA

    Sara Lόpez-Pintado

  7. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA

    Alain Borczuk

  8. Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA

    Doreen Hebert & Swarnali Acharyya

  9. Food Science and Human Nutrition Department, University of Florida, Gainesville, FL, USA

    Supak Jenkitkasemwong & Mitchell D. Knutson

  10. Deutsches Rheuma-Forschungszentrum Berlin, Osteoimmunology, Berlin, Germany

    Shintaro Hojyo

  11. Molecular and Cellular Physiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan

    Toshiyuki Fukada

  12. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA

    Swarnali Acharyya

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Contributions

G.W., A.K.B., W.M., C.C. and S.A. designed and performed the experiments. G.W., A.K.B., W.M. and S.A. wrote the manuscript. P.M.G. and M.A.H. provided human muscle samples from the Rapid Autopsy Program (RAP)-Pancreas at the University of Nebraska Medical Center. R.J. assisted with antibody purification. K.T., A.B., and D.H. provided pathological characterization and oversaw muscle samples collection at CUMC. M.K. performed the bioinformatics analysis and was supervised by R.D. S.L.-P. provided biostatistics consultation. S.H., S.J., M.D.K. and T.F. provided the Zip14-knockout mice and reagents. A.K.B. and S.A. conceived the project. S.A. supervised all research. All authors read the manuscript and approved the study.

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Correspondence to Swarnali Acharyya.

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Wang, G., Biswas, A.K., Ma, W. et al. Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle. Nat Med 24, 770–781 (2018). https://doi.org/10.1038/s41591-018-0054-2

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