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Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle


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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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.

Author information

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.

Competing interests

The authors declare no competing interests.

Correspondence to Swarnali Acharyya.

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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.