The Unique Metabolite Landscape of the Aged Microenvironment Dictates Melanoma Migratory and Invasive Capacity

Metastatic burden and organ failure are the root causes of mortality in patients with advanced melanoma; however, there is little known about the molecular drivers that enable early organ colonization and the formation of overt metastases. Patients over the age of 55 have a higher incidence of metastasis compared to younger patients independent of other prognostic factors. Metabolic dysregulation has been identified as a hallmark of aging; however, not much is known about how host cell metabolic reprogramming during aging contributes to melanoma motility, invasiveness, and metastatic capacity. Following metabolomics of host cells and melanoma cells in the context of aging and secondary validation, here we report that changes in bioavailable nutrients to melanoma cells occur in the aged tumor microenvironment (TME), which confer elevated melanoma cell motility and invasiveness. We identified novel transcriptomic and differential proteome signatures that expound the migratory and invasive differences observed in cells under distinct age-dependent metabolic environments. This work has important implications for our understanding of the metabolic determinants of melanoma migration and metastatic colonization during aging.