A novel SOX6 + melanoma cell subtype promotes early microsatellite invasion in Asian acral melanoma through fatty acid transport disorder

Acral melanoma (AM) is the predominant subtype of melanoma in Asians. Early detection and prevention can significantly improve patient outcomes; however, there is a lack of effective early biomarkers for predicting AM metastasis. Here, we employed single-cell and spatial transcriptomics analyses to investigate early microsatellite lesions of AM and identify biomarkers of invasiveness in these lesions. Our results characterize a highly immunosuppressive microenvironment and metabolic process shifts in early AM microsatellite lesions that promote the metastatic potential. The transcription factor SOX6 is overexpressed in microsatellite lesions and marks a population of highly invasive melanoma cells. The pro-invasive role of overexpressed SOX6 was validated in vivo and in vitro, including its ability to enhance tumor invasion by upregulating cellular glycolysis, disrupt fatty acid transport, and increase intracellular phosphatidylcholine content. This study suggests that SOX6-overexpressing melanoma cells are the main driver subpopulation promoting early invasion of AM and establishes SOX6 and fatty acid transport processes as biomarkers and potential therapeutic targets for early melanoma metastasis.