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.
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Article info
Publication history
Accepted:
February 12,
2023
Received in revised form:
January 29,
2023
Received:
September 22,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
CONFLICTS OF INTERESTS: None
DATA AVAILABILITY
The protein arrays data were submitted to NCBI GEO databasesGSE218501 and GSE221311. Gene and miRNA enrichment analysis as well as GO analysis added to Supplementary tables S1-S5. The rest of the data that support the findings of this study are available from the corresponding author upon reasonable request.
AUTHOR CONTRIBUTION
Conceptualization GL, CL, SG, Data curation GL, IS, SD, LL, PG, LS, RP, Formal Analysis GL, SD, LS, GS, NS, AB, JDH, funding-acquisition/" title="http://159.203.176.220/contributor-roles/funding-acquisition/">Funding acquisition JDH, SG, CL, Investigation GL, SD, JDH, CL, SG, Project administration SG, CL, JDH, Resources AB, Software GS, NS, Supervision CL, SG, Writing – original draft GL, CL, SG, Writing – review & editing GL, IS, SD, LL, PG LS, GS, RP, NS, AB, JDH, CL, SG.
Identification
Copyright
© 2023 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.
