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Merkel Cell Carcinoma-Derived Exosome-Shuttle MiR-375 Induces Fibroblast Polarization by Inhibition of RBPJ and P53

Authors: Kaiji Fan, Ivelina Spassova, Jan Gravemeyer, Cathrin Ritter, Kai Horny, Anja Lange, Thilo Gambichler, Niels Ødum, David Schrama, Dirk Schadendorf, Selma Ugurel & Jürgen C. Becker

Online: https://www.nature.com/articles/s41388-020-01576-6

Issue: Oncogene. 2021 Feb;40(5):980-996.


Merkel cell carcinoma (MCC) is a highly invasive and metastatic skin cancer. While high expression of miR-375 is a characteristic of MCC, it seems not to contribute to the malignant phenotype of MCC cells. miR-375 enrichment in MCC-derived extracellular vesicles suggests its intercellular signaling function. Here, we demonstrate that horizontally transferred miR-375 causes fibroblast polarization toward cancer-associated fibroblasts (CAFs). The polarization is evidenced by phenotypic changes and induction of α-SMA, CXCL2, and IL-1β. Fibroblast polarization is inhibited by specific antagomirs and mimicked by experimental miR-375 expression. Mechanistically, miR-375 downregulates RBPJ and p53, two key players regulating fibroblast polarization. In clinical MCC samples, in situ hybridization located miR-375 in CAFs, which correlated with high α-SMA protein and low RBPJ and TP53 expression; single-cell RNAseq revealed a disparate fibroblast polarization negatively correlating with p53 pathway-related gene expression. Thus, the functional role of miR-375 in MCC is to generate a pro-tumorigenic microenvironment by inducing fibroblast polarization.