Metabolic heterogeneity confers differences in melanoma metastatic potential.

Abstract

Metastasis requires cancer cells to undergo poorly-understood metabolic changes1–3. We found that metabolic differences among melanoma cells confer differences in metastatic potential as a result of differences in Monocarboxylate Transporter 1 (MCT1) function. In vivo isotope tracing in patient-derived xenografts revealed differences in nutrient handling between efficiently and inefficiently metastasizing melanomas, with circulating lactate being a more prominent source of tumor lactate in efficient metastasizers. Efficient metastasizers had higher MCT1 levels and MCT1 inhibition reduced lactate uptake. MCT1 inhibition had little effect on primary subcutaneous tumor growth but depleted circulating melanoma cells and reduced metastatic disease burden in patient-derived xenografts and in mouse melanomas. MCT1 inhibition suppressed the oxidative pentose phosphate pathway and increased ROS levels. Anti-oxidants blocked the effect of MCT1 inhibition on metastasis. MCT1high and MCT1−/low cells from the same melanomas had similar capacities to form subcutaneous tumors, but MCT1high cells formed more metastases after intravenous injection. Metabolic differences among cancer cells thus confer differences in metastatic potential as metastasizing cells depend upon MCT1 to manage oxidative stress.