Primary Melanoma miRNA Trafficking Induces Lymphangiogenesis

Abstract

Melanoma, the deadliest cutaneous tumor, initiates within the epidermis; during progression, cells invade into the dermis and become metastatic through the lymphatic and blood system. Prior to melanoma cells invasion into the dermis, an increased density of dermal lymphatic vessel is observed, generated by a not fully understood mechanism. Here, we show that, while at the primary epidermal stage (in-situ), melanoma cells secret extra cellular vesicles termed melanosomes, which are up taken by dermal lymphatic cells, leading to transcriptional and phenotypic pro-lymphangiogenic changes. Mechanistically, melanoma-derived melanosomes traffic mature let-7i to lymphatic endothelial cells, which mediate pro-lymphangiogenic phenotypic changes by the induction of type I interferon signaling. Further, transcriptome analysis upon treatments with melanosomes or let-7i reveal the enhancement of IFI6 expression in lymphatic cells. Since melanoma cells metastasize primarily via lymphatic vessels, our data suggest that blocking this lymphangiogenesis process by repressing either melanosome release or type I interferon signaling will prevent melanoma progression to the deadly metastatic stage.