Article | Published:

Oxidative stress inhibits distant metastasis by human melanoma cells

Nature volume 527, pages 186191 (12 November 2015) | Download Citation

Abstract

Solid cancer cells commonly enter the blood and disseminate systemically, but are highly inefficient at forming distant metastases for poorly understood reasons. Here we studied human melanomas that differed in their metastasis histories in patients and in their capacity to metastasize in NOD-SCID-Il2rg−/− (NSG) mice. We show that melanomas had high frequencies of cells that formed subcutaneous tumours, but much lower percentages of cells that formed tumours after intravenous or intrasplenic transplantation, particularly among inefficiently metastasizing melanomas. Melanoma cells in the blood and visceral organs experienced oxidative stress not observed in established subcutaneous tumours. Successfully metastasizing melanomas underwent reversible metabolic changes during metastasis that increased their capacity to withstand oxidative stress, including increased dependence on NADPH-generating enzymes in the folate pathway. Antioxidants promoted distant metastasis in NSG mice. Folate pathway inhibition using low-dose methotrexate, ALDH1L2 knockdown, or MTHFD1 knockdown inhibited distant metastasis without significantly affecting the growth of subcutaneous tumours in the same mice. Oxidative stress thus limits distant metastasis by melanoma cells in vivo.

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Acknowledgements

S.J.M. is a Howard Hughes Medical Institute (HHMI) Investigator, the Mary McDermott Cook Chair in Pediatric Genetics, the director of the Hamon Laboratory for Stem Cells and Cancer, and a Cancer Prevention and Research Institute of Texas Scholar. We thank K. Correll and M. Gross for mouse colony management; N. Loof and the Moody Foundation Flow Cytometry Facility. We thank N. Meireles and the University of Michigan Melanoma Biobank, for Biobank database and melanoma clinical data management.

Author information

Affiliations

  1. Children’s Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

    • Elena Piskounova
    • , Michalis Agathocleous
    • , Malea M. Murphy
    • , Zeping Hu
    • , Sara E. Huddlestun
    • , Zhiyu Zhao
    • , Ralph J. DeBerardinis
    •  & Sean J. Morrison
  2. Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

    • A. Marilyn Leitch
  3. Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109-2216, USA

    • Timothy M. Johnson
  4. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

    • Sean J. Morrison

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Contributions

E.P. and S.J.M. conceived the project, designed, and interpreted experiments. M.A. and R.J.D. participated in the design and interpretation of experiments related to metabolic mechanisms. E.P. performed all the experiments with technical assistance from S.E.H., metabolomics assistance from M.A and imaging assistance from M.M.M. Z.H. and M.A developed metabolomics methods. Z.Z. assisted with statistical analyses. A.M.L. and T.M.J. provided melanoma specimens and associated clinical data. E.P., M.A. and S.J.M wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Sean J. Morrison.

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  1. 1.

    Supplementary Information

    Supplementary Figure 1 shows the western blots for Figures 3a, 3h and Extended Data Figures 6f, 6g. Tumour measurements for Figures 2a, 3b, 3e and 3i are also shown.

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DOI

https://doi.org/10.1038/nature15726

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