Oxidative stress inhibits distant metastasis by human melanoma cells

Nature. 2015 Nov 12;527(7577):186-91. doi: 10.1038/nature15726. Epub 2015 Oct 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Female
  • Folic Acid / metabolism
  • Gene Knockdown Techniques
  • Humans
  • Male
  • Melanoma / blood
  • Melanoma / metabolism*
  • Melanoma / pathology*
  • Methotrexate / pharmacology
  • Methylenetetrahydrofolate Dehydrogenase (NADP) / deficiency
  • Methylenetetrahydrofolate Dehydrogenase (NADP) / metabolism
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Minor Histocompatibility Antigens
  • NADP / metabolism
  • Neoplasm Metastasis / prevention & control*
  • Neoplasm Transplantation
  • Oxidative Stress*
  • Oxidoreductases Acting on CH-NH Group Donors / deficiency
  • Oxidoreductases Acting on CH-NH Group Donors / metabolism


  • Antioxidants
  • Minor Histocompatibility Antigens
  • NADP
  • Folic Acid
  • Oxidoreductases Acting on CH-NH Group Donors
  • MTHFD1 protein, human
  • Methylenetetrahydrofolate Dehydrogenase (NADP)
  • formyltetrahydrofolate dehydrogenase
  • Methotrexate