🇬🇧 miR-146a-5p increases melanoma brain metastasis development by elevating Notch signaling

Abstract

Melanoma brain metastases (MBM) are a major clinical challenge due to the protective blood-brain barrier (BBB) and the brain’s unique microenvironment. We demonstrate that extracellular vesicle (EV)-associated miR-146a promotes MBM by activating astrocytes and enhancing Notch signaling through downregulation of NUMB. This creates a tumor-supportive inflammatory niche that facilitates metastatic growth.

Knockdown of miR-146a or treatment with deserpidine significantly reduces tumor burden and improves survival in mouse models. In parallel, miR-138, also enriched in tumor EVs, increases BBB permeability, potentially supporting metastatic seeding. Multimodal imaging and spatial transcriptomics reveal tumor-induced vascular changes, hypoxia, and altered neuronal signaling in EV-exposed
normal brain tissue.

Key transcriptomic responses involve VEGFB and hypoxic markers, suggesting exosome-driven reprogramming of the brain niche. These findings support a model where EV-delivered miRNAs establish a permissive environment for brain metastasis and highlight miR-146a as a promising therapeutic target.