Prostaglandin E2-driven dedifferentiation of Schwann cells leads to perineural invasion in pancreatic ductal adenocarcinoma

Perineural invasion (PNI), a prominent pathological feature of pancreatic ductal adenocarcinoma (PDAC), is closely associated with poor prognosis. Clarifying its mechanism is therefore critical for developing new therapies. Recent research has focused on the crosstalk between tumors and Schwann cells (SCs), particularly the role of SC dedifferentiation in facilitating PNI. In this study, by integrating RNA-seq, spatial transcriptomics, and single-cell analysis of clinical samples, we identified significant enrichment of dedifferentiated SCs and upregulation of key markers (p75NTR, SOX2, and c-Jun) in PNI regions. Moreover, PTGES was more highly expressed in the central region of the PNI than in the Other regions of the PNI. Coculture experiments revealed that PANC-1 and BxPC-3 cells enhanced SC dedifferentiation, and this process facilitated pancreatic Cancer cell malignancy. Furthermore, PTGES upregulation in the coculture system mediated prostaglandin E₂ (PGE₂) synthesis. Functional experiments revealed that PGE₂ drove morphological alterations in SCs-characterized by bipolar stretching-and elevated the expression of dedifferentiation markers, including p75NTR, c-Jun, SOX2, and GDNF. In the 3D coculture model, treatment with a PTGES inhibitor (CAY10526), siPTGES or PTGES-KO impaired the directional migration and neurite outgrowth of SCs toward PDAC cells. Mechanistically, PGE₂-stimulated SCs secrete elevated levels of LIF and ADAMTS-1, factors that promote extracellular matrix degradation and neural remodeling to facilitate tumor invasion. In summary, we delineate a novel paracrine axis in which PDAC-derived PGE₂ drives SC dedifferentiation and the production of proinvasive factors (LIF and ADAMTS-1), collectively establishing a microenvironment conducive to PNI. Our findings suggest that the PTGES-SC axis is a promising therapeutic target for inhibiting PNI in PDAC.