Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1.

    Lambert, A. W., Pattabiraman, D. R. & Weinberg, R. A. Emerging biological principles of metastasis. Cell 168, 670–691 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. 2.

    Massagué, J. & Obenauf, A. C. Metastatic colonization by circulating tumour cells. Nature 529, 298–306 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. 3.

    Waning, D. L. et al. Excess TGF-β mediates muscle weakness associated with bone metastases in mice. Nat. Med. 21, 1262–1271 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. 4.

    Becker, A. et al. Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer Cell 30, 836–848 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. 5.

    McAllister, S. S. & Weinberg, R. A. The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat. Cell Biol. 16, 717–727 (2014).

    Article  PubMed  CAS  Google Scholar 

  6. 6.

    Argilés, J. M., Busquets, S., Stemmler, B. & López-Soriano, F. J. Cancer cachexia: understanding the molecular basis. Nat. Rev. Cancer 14, 754–762 (2014).

    Article  PubMed  CAS  Google Scholar 

  7. 7.

    Fearon, K. C., Glass, D. J. & Guttridge, D. C. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab. 16, 153–166 (2012).

    Article  PubMed  CAS  Google Scholar 

  8. 8.

    Fearon, K., Arends, J. & Baracos, V. Understanding the mechanisms and treatment options in cancer cachexia. Nat. Rev. Clin. Oncol. 10, 90–99 (2013).

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    Baracos, V. E., Martin, L., Korc, M., Guttridge, D. C. & Fearon, K. C. H. Cancer-associated cachexia. Nat. Rev. Dis. Primers 4, 17105 (2018).

    Article  PubMed  Google Scholar 

  10. 10.

    Cohen, S., Nathan, J. A. & Goldberg, A. L. Muscle wasting in disease: molecular mechanisms and promising therapies. Nat. Rev. Drug Discov. 14, 58–74 (2015).

    Article  PubMed  CAS  Google Scholar 

  11. 11.

    Sandri, M. Protein breakdown in cancer cachexia. Semin. Cell Dev. Biol. 54, 11–19 (2016).

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    Penna, F., Busquets, S. & Argilés, J. M. Experimental cancer cachexia: evolving strategies for getting closer to the human scenario. Semin. Cell Dev. Biol. 54, 20–27 (2016).

    Article  PubMed  Google Scholar 

  13. 13.

    Dewys, W. D. et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Am. J. Med. 69, 491–497 (1980).

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    Aydemir, T. B. & Cousins, R. J. The multiple faces of the metal transporter ZIP14 (SLC39A14). J. Nutr. 148, 174–184 (2018).

    Article  PubMed  Google Scholar 

  15. 15.

    Finney, L. A. & O’Halloran, T. V. Transition metal speciation in the cell: insights from the chemistry of metal ion receptors. Science 300, 931–936 (2003).

    Article  PubMed  CAS  Google Scholar 

  16. 16.

    Lichten, L. A. & Cousins, R. J. Mammalian zinc transporters: nutritional and physiologic regulation. Annu. Rev. Nutr. 29, 153–176 (2009).

    Article  PubMed  Google Scholar 

  17. 17.

    Larsson, S., Karlberg, I., Selin, E., Daneryd, P. & Peterson, H. I. Trace element changes in serum and skeletal muscle compared to tumour tissue in sarcoma-bearing rats. In Vivo 1, 131–140 (1987).

    PubMed  CAS  Google Scholar 

  18. 18.

    Siren, P. M. & Siren, M. J. Systemic zinc redistribution and dyshomeostasis in cancer cachexia. J. Cachexia Sarcopenia Muscle 1, 23–33 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Talmadge, J. E. & Fidler, I. J. Enhanced metastatic potential of tumor cells harvested from spontaneous metastases of heterogeneous murine tumors. J. Natl. Cancer Inst. 69, 975–980 (1982).

    PubMed  CAS  Google Scholar 

  20. 20.

    Francia, G., Cruz-Munoz, W., Man, S., Xu, P. & Kerbel, R. S. Mouse models of advanced spontaneous metastasis for experimental therapeutics. Nat. Rev. Cancer 11, 135–141 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. 21.

    Fearon, K. C. Cancer cachexia: developing multimodal therapy for a multidimensional problem. Eur. J. Cancer 44, 1124–1132 (2008).

    Article  PubMed  CAS  Google Scholar 

  22. 22.

    Azoulay, E. et al. The prognosis of acute respiratory failure in critically ill cancer patients. Medicine (Baltimore) 83, 360–370 (2004).

    Article  Google Scholar 

  23. 23.

    Iguchi, H., Onuma, E., Sato, K., Sato, K. & Ogata, E. Involvement of parathyroid hormone–related protein in experimental cachexia induced by a human lung cancer–derived cell line established from a bone metastasis specimen. Int. J. Cancer 94, 24–27 (2001).

    Article  PubMed  CAS  Google Scholar 

  24. 24.

    Shum, A. M. et al. Cardiac and skeletal muscles show molecularly distinct responses to cancer cachexia. Physiol. Genomics 47, 588–599 (2015).

    Article  PubMed  CAS  Google Scholar 

  25. 25.

    Bonetto, A. et al. STAT3 activation in skeletal muscle links muscle wasting and the acute phase response in cancer cachexia. PLoS One 6, e22538 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. 26.

    Kwon, M. C. & Berns, A. Mouse models for lung cancer. Mol. Oncol. 7, 165–177 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. 27.

    Nguyen, D. X. et al. WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell 138, 51–62 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. 28.

    Xu, C. et al. Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell 25, 590–604 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. 29.

    Balkwill, F. TNF-α in promotion and progression of cancer. Cancer Metastasis Rev. 25, 409–416 (2006).

    Article  PubMed  CAS  Google Scholar 

  30. 30.

    Esposito, M., Guise, T. & Kang, Y. The biology of bone metastasis. Cold Spring Harb. Perspect. Med. a031252 (2017).

  31. 31.

    Cai, D. et al. IKKβ/NF-κβ activation causes severe muscle wasting in mice. Cell 119, 285–298 (2004).

    Article  PubMed  CAS  Google Scholar 

  32. 32.

    Guttridge, D. C., Mayo, M. W., Madrid, L. V., Wang, C. Y. & Baldwin, A. S. Jr. NF-κβ-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science 289, 2363–2366 (2000).

    Article  PubMed  CAS  Google Scholar 

  33. 33.

    Hojyo, S. et al. The zinc transporter SLC39A14/ZIP14 controls G-protein coupled receptor–mediated signaling required for systemic growth. PLoS One 6, e18059 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. 34.

    Liuzzi, J. P. et al. Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response. Proc. Natl. Acad. Sci. USA 102, 6843–6848 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. 35.

    He, W. A. et al. NF-κB-mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia. J. Clin. Invest. 123, 4821–4835 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. 36.

    Sabourin, L. A. & Rudnicki, M. A. The molecular regulation of myogenesis. Clin. Genet. 57, 16–25 (2000).

    Article  PubMed  CAS  Google Scholar 

  37. 37.

    Penna, F. et al. Muscle wasting and impaired myogenesis in tumor bearing mice are prevented by ERK inhibition. PLoS One 5, e13604 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. 38.

    Liu, N. et al. Requirement of MEF2A, C, and D for skeletal muscle regeneration. Proc. Natl. Acad. Sci. USA 111, 4109–4114 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. 39.

    Skapek, S. X., Rhee, J., Spicer, D. B. & Lassar, A. B. Inhibition of myogenic differentiation in proliferating myoblasts by cyclin D1-dependent kinase. Science 267, 1022–1024 (1995).

    Article  PubMed  CAS  Google Scholar 

  40. 40.

    Wei, Q. & Paterson, B. M. Regulation of MyoD function in the dividing myoblast. FEBS Lett. 490, 171–178 (2001).

    Article  PubMed  CAS  Google Scholar 

  41. 41.

    Glass, D. J. Signaling pathways perturbing muscle mass. Curr. Opin. Clin. Nutr. Metab. Care 13, 225–229 (2010).

    Article  PubMed  CAS  Google Scholar 

  42. 42.

    Roberts, B. M. et al. Diaphragm and ventilatory dysfunction during cancer cachexia. FASEB J. 27, 2600–2610 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. 43.

    Cohen, S. et al. During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation. J. Cell Biol. 185, 1083–1095 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. 44.

    Clarke, B. A. et al. The E3 ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle. Cell Metab. 6, 376–385 (2007).

    Article  PubMed  CAS  Google Scholar 

  45. 45.

    Acharyya, S. et al. Cancer cachexia is regulated by selective targeting of skeletal muscle gene products. J. Clin. Invest. 114, 370–378 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. 46.

    Gupta, S. K., Shukla, V. K., Vaidya, M. P., Roy, S. K. & Gupta, S. Serum and tissue trace elements in colorectal cancer. J. Surg. Oncol. 52, 172–175 (1993).

    Article  PubMed  CAS  Google Scholar 

  47. 47.

    Russell, S. T., Siren, P. M., Siren, M. J. & Tisdale, M. J. The role of zinc in the anti-tumour and anti-cachectic activity of d-myo-inositol 1,2,6-triphosphate. Br. J. Cancer 102, 833–836 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. 48.

    Cousins, R. J. & Leinart, A. S. Tissue-specific regulation of zinc metabolism and metallothionein genes by interleukin 1. FASEB J. 2, 2884–2890 (1988).

    Article  PubMed  CAS  Google Scholar 

  49. 49.

    Summermatter, S. et al. Blockade of metallothioneins 1 and 2 increases skeletal muscle mass and strength. Mol. Cell. Biol. 37, e00305–16 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Crawford, A. J. & Bhattacharya, S. K. Excessive intracellular zinc accumulation in cardiac and skeletal muscles of dystrophic hamsters. Exp. Neurol. 95, 265–276 (1987).

    Article  PubMed  CAS  Google Scholar 

  51. 51.

    Lecker, S. H. et al. Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J. 18, 39–51 (2004).

    Article  PubMed  CAS  Google Scholar 

  52. 52.

    Kang, Y. et al. Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc. Natl. Acad. Sci. USA 102, 13909–13914 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. 53.

    Schiaffino, S., Dyar, K. A., Ciciliot, S., Blaauw, B. & Sandri, M. Mechanisms regulating skeletal muscle growth and atrophy. FEBS J. 280, 4294–4314 (2013).

    Article  PubMed  CAS  Google Scholar 

  54. 54.

    Eley, H. L., Skipworth, R. J., Deans, D. A., Fearon, K. C. & Tisdale, M. J. Increased expression of phosphorylated forms of RNA-dependent protein kinase and eukaryotic initiation factor 2α may signal skeletal muscle atrophy in weight-losing cancer patients. Br. J. Cancer 98, 443–449 (2008).

    Article  PubMed  CAS  Google Scholar 

  55. 55.

    Schmitt, T. L. et al. Activity of the Akt-dependent anabolic and catabolic pathways in muscle and liver samples in cancer-related cachexia. J. Mol. Med. (Berl.) 85, 647–654 (2007).

    Article  CAS  Google Scholar 

  56. 56.

    Yamasaki, S. et al. Zinc is a novel intracellular second messenger. J. Cell Biol. 177, 637–645 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. 57.

    Andreini, C., Bertini, I. & Rosato, A. Metalloproteomes: a bioinformatic approach. Acc. Chem. Res. 42, 1471–1479 (2009).

    Article  PubMed  CAS  Google Scholar 

  58. 58.

    Dumont, N. A., Wang, Y. X. & Rudnicki, M. A. Intrinsic and extrinsic mechanisms regulating satellite cell function. Development 142, 1572–1581 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. 59.

    Talbert, E. E. & Guttridge, D. C. Impaired regeneration: a role for the muscle microenvironment in cancer cachexia. Semin. Cell Dev. Biol. 54, 82–91 (2016).

    Article  PubMed  Google Scholar 

  60. 60.

    Wallace, G. Q. & McNally, E. M. Mechanisms of muscle degeneration, regeneration, and repair in the muscular dystrophies. Annu. Rev. Physiol. 71, 37–57 (2009).

    Article  PubMed  CAS  Google Scholar 

  61. 61.

    Jahchan, N. S. et al. A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors. Cancer Discov. 3, 1364–1377 (2013).

    Article  PubMed  CAS  Google Scholar 

  62. 62.

    Acharyya, S. et al. Dystrophin glycoprotein complex dysfunction: a regulatory link between muscular dystrophy and cancer cachexia. Cancer Cell 8, 421–432 (2005).

    Article  PubMed  CAS  Google Scholar 

  63. 63.

    Blanco, M. A. et al. Global secretome analysis identifies novel mediators of bone metastasis. Cell Res. 22, 1339–1355 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. 64.

    Polge, C. et al. Muscle actin is polyubiquitinylated in vitro and in vivo and targeted for breakdown by the E3 ligase MuRF1. FASEB J. 25, 3790–3802 (2011).

    Article  PubMed  CAS  Google Scholar 

  65. 65.

    Gee, K. R., Zhou, Z. L., Qian, W. J. & Kennedy, R. Detection and imaging of zinc secretion from pancreatic β-cells using a new fluorescent zinc indicator. J. Am. Chem. Soc. 124, 776–778 (2002).

    Article  PubMed  CAS  Google Scholar 

  66. 66.

    Dalal, B. I., Keown, P. A. & Greenberg, A. H. Immunocytochemical localization of secreted transforming growth factor-β1 to the advancing edges of primary tumors and to lymph node metastases of human mammary carcinoma. Am. J. Pathol. 143, 381–389 (1993).

    PubMed  PubMed Central  CAS  Google Scholar 

  67. 67.

    Jenkitkasemwong, S. et al. slc39a14 is required for the development of hepatocellular iron overload in murine models of hereditary hemochromatosis. Cell Metab. 22, 138–150 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. 68.

    Burkholder, T., Foltz, C., Karlsson, E., Linton, C. G. & Smith, J. M. Health evaluation of experimental laboratory mice. Curr. Protoc. Mouse Biol. 2, 145–165 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    DuPage, M., Dooley, A. L. & Jacks, T. Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase. Nat. Protoc. 4, 1064–1072 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. 70.

    Ohly, P., Dohle, C., Abel, J., Seissler, J. & Gleichmann, H. Zinc sulphate induces metallothionein in pancreatic islets of mice and protects against diabetes induced by multiple low doses of streptozotocin. Diabetologia 43, 1020–1030 (2000).

    Article  PubMed  CAS  Google Scholar 

  71. 71.

    Buclez, P. O. et al. Rapid, scalable, and low-cost purification of recombinant adeno-associated virus produced by baculovirus expression vector system. Mol. Ther. Methods Clin. Dev. 3, 16035 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. 72.

    Vogler, T. O., Gadek, K. E., Cadwallader, A. B., Elston, T. L. & Olwin, B. B. Isolation, culture, functional assays, and immunofluorescence of myofiber-associated satellite cells. Methods Mol. Biol. 1460, 141–162 (2016).

    Article  PubMed  Google Scholar 

  73. 73.

    Motohashi, N., Asakura, Y. & Asakura, A. Isolation, culture, and transplantation of muscle satellite cells. J. Vis. Exp. 86, 50846 (2014).

    Google Scholar 

  74. 74.

    Acharyya, S. et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150, 165–178 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. 75.

    Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2–ΔΔCT method. Methods 25, 402–408 (2001).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  76. 76.

    Volodin, A., Kosti, I., Goldberg, A. L. & Cohen, S. Myofibril breakdown during atrophy is a delayed response requiring the transcription factor PAX4 and desmin depolymerization. Proc. Natl. Acad. Sci. USA 114, E1375–E1384 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. 77.

    Cosper, P. F. & Leinwand, L.A. Myosin heavy chain is not selectively decreased in murine cancer cachexia. Int. J. Cancer 130, 2722–2727 (2012).

    Article  PubMed  CAS  Google Scholar 

  78. 78.

    Liberzon, A. et al. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 1, 417–425 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. 79.

    Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

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.

Author information

Affiliations

Authors

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.

Corresponding author

Correspondence to Swarnali Acharyya.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Tables 1–7

Reporting Summary

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Further reading