Abstract

Perineural invasion (PNI), as a prominent feature of pancreatic ductal adenocarcinoma, is closely related to poor prognosis and urgently needs to be investigated mechanisms to find effective intervention measures. PIEZO1, a mechanically activated cation channel, has emerged as a protein of interest in cancer research. This study aimed to elucidate the role of PIEZO1 in pancreatic cancer, with a particular focus on its association with neural invasion. Spatial transcriptome analysis of pancreatic cancer tissue samples revealed that PIEZO1 expression was significantly elevated in perineural invasion areas compared to non-perineural regions. Furthermore, PIEZO1 expression exhibited a gradient decrease from the vicinity of perineural invasion sites to more distant areas. Functional analyses and co-culture assays revealed that PIEZO1 activation consolidates a neurotrophic, neuroinvasive phenotype in pancreatic cancer cells. Transcriptomic analysis linked PIEZO1 to the Hippo signaling pathway, identifying YAP1 as a potential transcriptional target. In vivo studies showed that PIEZO1 inhibition reduced PNI and liver metastasis in mice. Collectively, these results identify PIEZO1 as a key contributor to PNI in pancreatic cancer and suggest that the PIEZO1-YAP1 axis warrants further exploration as a candidate signaling module for future therapeutic strategies.