MiR-183-5p-enriched Endothelial Extracellular Vesicles: Key Players in Pre-Metastatic Niche Formation in Breast Cancer?

Breast cancer (BC) remains one of the most prevalent cancers globally. Although primary tumors can often be treated successfully, metastatic BC remains incurable and is the primary cause of mortality. Previous work from our group discovered that endothelial cell-derived extracellular vesicles (EVs) enriched in miR-142-5p, miR-183-5p, and miR-222-3p—collectively termed “miR-TAM”— promote macrophage polarization towards a pro-tumorigenic M2-like phenotype, thereby enhancing tumor growth in murine BC models. However, the role of miR-TAM in metastasis, particularly in pre-metastatic niche (PMN) formation, has not been investigated.
To address this gap, we conducted both in vitro and in vivo studies. We treated macrophage and fibroblast cell lines—key contributors to PMN development—with miR-TAM-enriched EVs. This treatment led to a marked upregulation of several pro-tumorigenic genes, including Csf3, Cxcl1, Col3a1, Il-1β, and Ccl3. In parallel, we administered miR-TAM-enriched EVs peritumourally every two days to 4T1 tumour-bearing mice. Strikingly, treated mice exhibited a significant reduction in pulmonary CD4⁺ and CD8⁺ T cell populations, indicating the establishment of an immunosuppressive microenvironment conducive to metastatic colonization.
In conclusion, our findings reveal a previously unrecognized role of miR-TAM-enriched endothelial EVs in promoting PMN formation and metastatic progression in breast cancer. These insights suggest that miR-TAM-enriched EVs may represent novel therapeutic targets to intercept metastasis in BC patients.