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

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

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

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

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).

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).

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

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

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).

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).

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

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).

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

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

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).

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

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).

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

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).

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).

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

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

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).

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

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).

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

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

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).

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

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

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

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).

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).

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).

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).

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

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

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

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).

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

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

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

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).

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).

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

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).

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).

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).

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

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).

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).

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).

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).

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).

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).

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

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

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

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).

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).

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).

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

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

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).

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).

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).

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).

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).

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).

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).

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).

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).

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

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

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).

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).

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).

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