Periostin-positive stellate cells associated with perineural invasion in pancreatic adenocarcinoma

Perineural invasion (PNI) is a hallmark of pancreatic ductal adenocarcinoma (PDAC) associated with poor prognosis. Despite its clinical significance, the specific cellular and molecular mechanisms driving PNI in PDAC remain poorly defined. In this study, we analyzed transcriptomic data from approximately 60,000 single cells across 24 PDAC biopsy specimens to characterize the cellular composition and signaling networks associated with PNI. We found that pancreatic stellate cells (PSCs) expressing high levels of Periostin (POSTN), collagens, and metalloproteinases are enriched in PNI-positive samples, suggesting an active role in extracellular matrix remodeling and tumor invasion. Spatial transcriptomics revealed that these POSTN + PSCs are located adjacent to tumor cells in invasive regions but are more distant in non-invasive samples. Invasive tumors show a coordinated expression pattern involving ANXA1 in tumor cells, SPP1 and PLAU in PSCs, and their receptors in myeloid cells, supporting a signaling axis that promotes perineural invasion. This spatial arrangement indicates that POSTN + PSCs are not merely bystanders but active participants in driving tumor infiltration and perineural dissemination. Together, these findings reveal coordinated multicellular programs that underlie tumor invasion and spread in PDAC, offering new insights into its aggressive biology.