snRNA-seq of acral melanoma reveals heterogeneity and identifies novel progression marker and cancer-associated fibroblasts subpopulation.

Acral melanoma (AM) is characterized by a high incidence of distant metastasis. Although the genomic characterization of AM has been explored, the landscape of AM in different stages is still a critical factor to be researched. We performed single-nucleus RNA sequencing analysis in three nevi, seven primary AM, four skin metastases, and three lymph node metastasis specimens. Cell subpopulations were characterized. The identified marker was verified in clinical samples, and the function was further validated by in vitro and in vivo experiments through establishing a knockdown cell line. A total of 13 types of cells were identified from 17 samples. Ten cancer cell subtypes were profiled through comprehensive analysis. Analysis identified Cancer cells_TGFBI to be the potential progressive subpopulation, and SERPINE2 was the top differentially expressed gene. SERPINE2 knockdown significantly suppressed melanoma cell growth and invasion, and downregulated the EMT pathway. Cancer-associated fibroblast (CAF) had the second largest number of cells. A new cluster, Fibroblast_TNXB, was identified and had potential correlation with melanocyte differentiation and development. The above findings demonstrated the tumor heterogeneity of AM. SERPINE2 had the potential to be a therapeutic target for melanoma, and Fibroblast_TNXB may link to melanocytic differentiation, highlighting new microenvironmental crosstalk in AM.