Pancreatic cancer cells infiltrate nerves through TGFbeta1-driven perineural epithelial-to-mesenchymal-like transdifferentiation

Neural invasion is a prognostic hallmark of pancreatic ductal adenocarcinoma (PDAC), yet the underlying mechanisms behind the disruption of perineural barriers and access of cancer cells into intrapancreatic nerves remain poorly understood. This study aimed to investigate the role of epithelial-mesenchymal transformation (EMT) in perineural epithelial cells during neural invasion.Histopathological analysis of human and murine primary tumors using perineurium-specific GLUT1 antibody revealed a reduction in perineural integrity, which positively correlated with the extent of neural invasion in human PDAC cases. Human pancreatic cancer cell lines were found to secrete TGFbeta1, which induced EMT of perineural epithelial cells, characterized by the loss of epithelial markers (CK19-9) and the acquisition of mesenchymal markers (alphaSMA, N-Cadherin). Additionally, these transitioning perineural epithelial cells demonstrated increased matrix-degrading capabilities through the upregulation of matrix-metalloproteases 3 and 9 via SMAD2. In an autochthonous mouse model with elevated endogenous TGFbeta1 levels in addition to oncogenic Kras activation (Ptf1a^Cre/+, LSL-Kras^G12D/+, LSL-R26^Tgfβ/+), decreased perineural integrity could be reproduced in vivo.Collectively, these findings underscore the role played by TGFbeta1-overexpressing pancreatic cancer cells in the dismantling of perineural barriers during neural invasion.