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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. Before melanoma cell invasion into the dermis, an increased density of dermal lymphatic vessels is observed, generated by a mechanism which is not fully understood. In this study, we show that, while at the primary epidermal stage (in situ), melanoma cells secrete extracellular vesicles termed melanosomes, which are uptaken 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 IFN signaling. Furthermore, transcriptome analysis upon treatment with melanosomes or let-7i reveals the enhancement of IFI6 expression in lymphatic cells. Because melanoma cells metastasize primarily via lymphatic vessels, our data suggest that blocking lymphangiogenesis by repressing either melanosome release or type I IFN signaling will prevent melanoma progression to the deadly metastatic stage., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Sclerodermoid graft-versus-host disease (GVHD) is the most severe form of chronic GVHD (cGVHD) and represents a considerable therapeutic challenge. Due to the scarcity of human studies on sclerodermoid cGVHD, the pathogenesis of this entity is not fully understood., Objective: To identify the differential expression of fibrosis-related genes in skin lesions of human lichenoid and sclerodermoid cGVHD and to assess the expression of their corresponding proteins., Methods: PCR array analysis was performed on RNA extracted from three skin biopsies of sclerodermoid cGVHD patients and three normal skin samples, for fibrosis-related gene expression profiles followed by evaluation of their corresponding protein expressions. The expressions of Tissue inhibitor of metalloproteinase 3 (TIMP3), matrix metalloproteinase 1 (MMP1), TIMP1, and TIMP2 were further studied by immunohistochemistry. Demographic, clinical and immunohistochemical parameters of the two cGVHD groups and the control group were compared. The Pearson correlation coefficient was used to assess the correlation between data among the study groups., Results: We identified 44 upregulated and 14 downregulated genes in the skin samples of sclerodermoid cGVHD compared to the control group. TIMP3 was positive in 13/21 biopsies of cGVHD and in one biopsy of the control group. The average staining intensity was significantly higher in the cGVHD group compared to the control group. TIMP3 was expressed mainly in dermal blood vessels. cGVHD specimens with positive TIMP3 staining had a statistically significantly higher total microvascular area than the negative specimens., Conclusion: TIMP3 levels are increased in both subtypes of cGVHD and are associated with increased dermal vascularity., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2022 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)