Oxidative stress inhibits distant metastasis by human melanoma cells

Elena Piskounova, Michalis Agathocleous, Malea M. Murphy, Zeping Hu, Sara E. Huddlestun, Zhiyu Zhao, A. Marilyn Leitch, Timothy M. Johnson, Ralph J. DeBerardinis and Sean J. Morrison ()
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Elena Piskounova: University of Texas Southwestern Medical Center
Michalis Agathocleous: University of Texas Southwestern Medical Center
Malea M. Murphy: University of Texas Southwestern Medical Center
Zeping Hu: University of Texas Southwestern Medical Center
Sara E. Huddlestun: University of Texas Southwestern Medical Center
Zhiyu Zhao: University of Texas Southwestern Medical Center
A. Marilyn Leitch: University of Texas Southwestern Medical Center
Timothy M. Johnson: University of Michigan
Ralph J. DeBerardinis: University of Texas Southwestern Medical Center
Sean J. Morrison: University of Texas Southwestern Medical Center

Nature, 2015, vol. 527, issue 7577, 186-191

Abstract: 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.

Date: 2015
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DOI: 10.1038/nature15726

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