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.
People with pale skin, red hair, freckles, and an inability to tan-the “redhair/fairskin” phenotype- are at highest risk of developing melanoma, compared to all other pigmentation types1.,Genetically, this phenotype is frequently the product of inactivating polymorphisms in the Melanocortin 1 receptor (MC1R) gene.,MC1R encodes a cAMP stimulating G-protein coupled receptor that controls pigment production.,Minimal receptor activity, as in redhair/fairskin polymorphisms, produces red/yellow pheomelanin pigment, while increasing MC1R activity stimulates production of black/brown eumelanin2.,Pheomelanin has weak UV shielding capacity relative to eumelanin and has been shown to amplify UVA-induced reactive oxygen species (ROS) 3-5.,Several observations, however, complicate the assumption that melanoma risk is completely UV dependent.,For example, unlike non-melanoma skin cancers, melanoma is not restricted to sun-exposed skin and UV signature mutations are infrequently oncogenic drivers6.,While linkage of melanoma risk to UV exposure is beyond doubt, UV-independent events are also likely to play a significant role1,7.,Here, we introduced into mice carrying an inactivating mutation in the Mc1r gene (who exhibit a phenotype analogous to redhair/fairskin humans), a conditional, melanocyte-targeted allele of the most commonly mutated melanoma oncogene, BRafV600E.,We observed a high incidence of invasive melanomas without providing additional gene aberrations or UV exposure.,To investigate the mechanism of UV-independent carcinogenesis, we introduced an albino allele, which ablates all pigment production on the Mc1r e/e background.,Selective absence of pheomelanin synthesis was protective against melanoma development.,In addition, normal Mc1re/e mouse skin was found to have significantly greater oxidative DNA and lipid damage than albino-Mc1re/e mouse skin.,These data suggest that the pheomelanin pigment pathway produces UV-independent carcinogenic contributions to melanomagenesis by a mechanism of oxidative damage.,While UV protection remains important, additional strategies may be required for optimal melanoma prevention.