MCU-dependent negative sorting of miR-4488 to extracellular vesicles enhances angiogenesis and promotes breast cancer metastatic colonization

Based on Stephen Paget’s well-established theory, both cell-autonomous and non-cell-autonomous mechanisms are crucial for metastasis. Although the mitochondrial calcium uniporter (MCU) has been suggested to be involved in breast cancer (BC) progression via cell-autonomous mechanisms, whether it assists the metastasis of BC cells through non-cell-autonomous mechanisms remains unclear. This study aimed to demonstrate that the MCU regulates BC metastatic colonization via non-cell-autonomous mechanisms. The results suggested that extracellular vesicles (EVs) derived from MCU-downregulated MDA-MB-231 cells suppressed angiogenesis in the metastatic niche in a nude mouse model, thereby hindering the colonization of BC cells. Mechanistically, we revealed that the MCU negatively correlated with miR-4488 in EVs derived from BC cells. Significantly, miR-4488 was determined to suppress angiogenesis of vascular endothelial cells by directly targeting angiogenic CX3CL1. Furthermore, we identified miR-4488 as being significantly downregulated in serum EVs from patients with triple-negative BC. Hence, this study suggests that MCU-dependent negative sorting of miR-4488 to EVs enhances angiogenesis in the metastatic niche and, thus, favors the metastatic colonization of BC cells.