Abstract
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.
Highlights
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine (NE) skin cancer with an estimated mortality rate of ~40% [1]
TE-7 was expressed at low levels in most stromal cells, with a few exceptions. α-SMA was expressed by fibroblast-like cells and pericytes in the vicinity of blood vessels and was often colocalized with CAV1
We reveal the heterogeneity of fibroblasts in the stroma of MCC lesions, which reflects a spectrum of polarization toward a cancer-associated fibroblasts (CAFs)
Summary
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine (NE) skin cancer with an estimated mortality rate of ~40% [1]. MCC carcinogenesis is associated with the oncogenic Merkel cell polyomavirus (MCPyV), while in the other cases, it is UV-driven [1]. While the role of tumorinfiltrating lymphocytes has been studied in detail [3,4,5], the characteristics of tumor-associated fibroblasts in the MCC microenvironment are largely unexplored. Fibroblasts are very plastic cells that may contribute to tumor progression and metastasis depending on their polarization and activation states [6]. Tumor-promoting fibroblasts are termed cancer-associated fibroblasts (CAFs). Cancer cell-derived stimuli are assumed to be the Merkel cell carcinoma-derived exosome-shuttle miR-375 induces fibroblast polarization by inhibition of
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