Cell Death Dis

Metastasis, the colonization of distant organs by cells derived from primary cancer, is the leading cause of mortality in pancreatic adenocarcinoma (PAAD). Growing evidence indicates that cancer-derived exosomes play pivotal roles in facilitating cancer metastasis by promoting pre-metastatic niche formation. However, the contribution of PAAD-derived exosomal microRNAs (MiRNAs) to this process remains poorly characterized. In this study, we identified specific PAAD-derived exosomal miRNAs involved in metastatic progression. Sequencing of small RNAs extracted from circulating exosomes derived from patients with metastatic or non-metastatic PAAD revealed that miR-92a-3p is associated with a metastatic phenotype. We demonstrated that exosomal miR-92a-3p facilitates cancer cells' extravasation and lung metastasis by disrupting vascular barrier integrity. Mechanistically, exosomal miR-92a-3p directly inhibits the tumor suppressor disabled homolog 2 interacting protein (DAB2IP), thereby activating the PI3K-AKT signaling cascade in endothelial cells (ECs). This activation attenuates expression of intracellular junction markers and stimulates endothelial nitric oxide synthase, leading to increased vascular permeability. Our findings suggest that targeting miR-92a-3p could represent a potential strategy to reduce metastasis in PAAD.