The exosomal miRNA-3184-3p derived from highly metastatic melanoma cells promotes metastatic competency via the positive feedback loop of NLK/Wnt/S100A11.

Protein secretion and extracellular vesicles represent distinct mechanisms through which cancer cells and stromal cells interact to modify the tumor microenvironment. However, most studies on these mechanisms have predominantly focused on elucidating the impact of cancer cells on stromal cells, leaving the interactions between cancer cells and adjacent cancer cells relatively unexplored. We utilized a heterogeneous melanoma metastasis cell model that our laboratory previously developed, comprising POL (Polymetastatic) cells with high metastatic potential and OL (Oligometastatic) cells with low metastatic potential. We applied bioinformatics methods to investigate this model. Our findings reveal that POL cells can secrete exosome-encapsulated miRNA-3184-3p into OL cells. Subsequently, this process targets and inhibits the Nlk gene, activating the Wnt/β-catenin signaling pathway, ultimately promoting the secretion of S100A11 protein by OL cells into the tumor microenvironment. Upon internalization by POL cells, S100A11 further enhances their metastatic capabilities, increasing the intracellular and exosomal content of miRNA-3184-3p. Consequently, a positive feedback loop is established between POL and OL cells, resulting in the continuous malignant progression of the tumor. These findings provide valuable insights into melanoma cell interactions and propose new therapeutic strategies for targeting melanoma metastasis.