Metabolic heterogeneity confers differences in melanoma metastatic potential

Alpaslan Tasdogan, Brandon Faubert, Vijayashree Ramesh, Jessalyn M. Ubellacker, Bo Shen, Ashley Solmonson, Malea M. Murphy, Zhimin Gu, Wen Gu, Misty Martin, Stacy Y. Kasitinon, Travis Vandergriff, Thomas P. Mathews, Zhiyu Zhao, Dirk Schadendorf, Ralph J. DeBerardinis () and Sean J. Morrison ()
Additional contact information
Alpaslan Tasdogan: University of Texas Southwestern Medical Center
Brandon Faubert: University of Texas Southwestern Medical Center
Vijayashree Ramesh: University of Texas Southwestern Medical Center
Jessalyn M. Ubellacker: University of Texas Southwestern Medical Center
Bo Shen: University of Texas Southwestern Medical Center
Ashley Solmonson: University of Texas Southwestern Medical Center
Malea M. Murphy: University of Texas Southwestern Medical Center
Zhimin Gu: University of Texas Southwestern Medical Center
Wen Gu: University of Texas Southwestern Medical Center
Misty Martin: University of Texas Southwestern Medical Center
Stacy Y. Kasitinon: University of Texas Southwestern Medical Center
Travis Vandergriff: University of Texas Southwestern Medical Center
Thomas P. Mathews: University of Texas Southwestern Medical Center
Zhiyu Zhao: University of Texas Southwestern Medical Center
Dirk Schadendorf: University Duisburg-Essen, Essen and German Cancer Consortium (DKTK)
Ralph J. DeBerardinis: University of Texas Southwestern Medical Center
Sean J. Morrison: University of Texas Southwestern Medical Center

Nature, 2020, vol. 577, issue 7788, 115-120

Abstract: Abstract Metastasis requires cancer cells to undergo metabolic changes that are poorly understood1–3. Here we show that metabolic differences among melanoma cells confer differences in metastatic potential as a result of differences in the function of the MCT1 transporter. In vivo isotope tracing analysis in patient-derived xenografts revealed differences in nutrient handling between efficiently and inefficiently metastasizing melanomas, with circulating lactate being a more prominent source of tumour lactate in efficient metastasizers. Efficient metastasizers had higher levels of MCT1, and inhibition of MCT1 reduced lactate uptake. MCT1 inhibition had little effect on the growth of primary subcutaneous tumours, but resulted in depletion of circulating melanoma cells and reduced the metastatic disease burden in patient-derived xenografts and in mouse melanomas. In addition, inhibition of MCT1 suppressed the oxidative pentose phosphate pathway and increased levels of reactive oxygen species. Antioxidants blocked the effects of MCT1 inhibition on metastasis. MCT1high and MCT1−/low cells from the same melanomas had similar capacities to form subcutaneous tumours, but MCT1high cells formed more metastases after intravenous injection. Metabolic differences among cancer cells thus confer differences in metastatic potential as metastasizing cells depend on MCT1 to manage oxidative stress.

Date: 2020
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DOI: 10.1038/s41586-019-1847-2

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