BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) exhibits a high frequency of neural invasion (NI). Schwann cells (SCs) have been shown to be reprogrammed to facilitate cancer cell migration and invasion into nerves. Since extracellular vesicles (EVs) affect the tumour microenvironment and promote metastasis, the present study analysed the involvement of EVs from pancreatic cancer cells and their microenvironment in altering SC phenotype as part of the early events in the process of NI. METHODS: EVs were isolated from human/murine PDAC cells, pancreatic stellate cells (PSCs), human tissues and plasma to perform a novel 3D migration assay, qRT-PCR and western blot. Kaplan-Meier and Cox regression analyses were employed to evaluate the clinical potential of plasma EV-derived candidate from 165 PDAC patients. RESULTS: The EVs from PDAC cells, PSCs derived from human tumour tissues, other cell types in the tumour microenvironment from tumour tissues and circulating plasma act as drivers of a pro-migratory phenotype of SCs by inducing dedifferentiation in SCs. Notably, p75NTR expression was upregulated in the plasma-derived EVs from patients with NI (Pn1) relative to those without NI (Pn0). High expression of plasma-derived EV p75NTR correlated with reduced overall survival and was identified as an independent prognostic factor. CONCLUSIONS: These findings suggest that EV-mediated SC migration underlies the interactions contributing to PDAC-associated NI with implications for improved outcome and therapeutic strategy.