@article{b8338022fc5e46829443fd8bad0be002,
title = "Metabolic heterogeneity confers differences in melanoma metastatic potential",
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.",
author = "Alpaslan Tasdogan and Brandon Faubert and Vijayashree Ramesh and Ubellacker, {Jessalyn M.} and Bo Shen and Ashley Solmonson and Murphy, {Malea M.} and Zhimin Gu and Wen Gu and Misty Martin and Kasitinon, {Stacy Y.} and Travis Vandergriff and Mathews, {Thomas P.} and Zhiyu Zhao and Dirk Schadendorf and DeBerardinis, {Ralph J.} and Morrison, {Sean J.}",
note = "Funding Information: Acknowledgements S.J.M. is a Howard Hughes Medical Institute (HHMI) Investigator, the Mary McDermott Cook Chair in Pediatric Genetics, the Kathryn and Gene Bishop Distinguished Chair in Pediatric Research, the director of the Hamon Laboratory for Stem Cells and Cancer, and a Cancer Prevention and Research Institute of Texas Scholar. R.J.D. is an HHMI Investigator, the Robert L. Moody, Sr. Faculty Scholar at UT Southwestern and Joel B. Steinberg, M.D. Chair in Pediatrics. The research was supported by the Cancer Prevention and Research Institute of Texas (RP170114 and RP180778), the National Institutes of Health (R35 CA220449; U01 CA228608) and the Robert A. Welch Foundation (I-1733). A.T. was supported by the Else Kr{\"o}ner-Forschungskolleg and the Leopoldina Fellowship Program (LPDS 2016-16) of the German National Academy of Sciences. B.F. was supported by a postdoctoral fellowship from the Canadian Institutes of Health Research (MFE 140911). B.S. and A.S. were supported by Ruth L. Kirschstein National Research Service Award Postdoctoral Fellowships from the National Heart, Lung, and Blood Institute (F32 HL139016-01) and the National Institute of Child Health and Human Development (F32 HD096786-01). We thank A. Gross for mouse colony management as well as N. Loof and the Moody Foundation Flow Cytometry Facility.",
year = "2020",
month = jan,
day = "2",
doi = "10.1038/s41586-019-1847-2",
language = "English (US)",
volume = "577",
pages = "115--120",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7788",
}