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Nature. 2020 Jan;577(7788):115-120. doi: 10.1038/s41586-019-1847-2. Epub 2019 Dec 18.

Metabolic heterogeneity confers differences in melanoma metastatic potential.

Author information

1
Children's Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
2
Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
3
Department of Dermatology, University Hospital, University Duisburg-Essen, Essen and German Cancer Consortium (DKTK), Heidelberg, Germany.
4
Children's Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA. ralph.deberardinis@UTSouthwestern.edu.
5
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA. ralph.deberardinis@UTSouthwestern.edu.
6
Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA. ralph.deberardinis@UTSouthwestern.edu.
7
Children's Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA. sean.morrison@UTSouthwestern.edu.
8
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA. sean.morrison@UTSouthwestern.edu.

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.

PMID:
31853067
PMCID:
PMC6930341
[Available on 2020-06-18]
DOI:
10.1038/s41586-019-1847-2

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