SPARC is associated with tumor nerve stroma interactions and perineural invasion in pancreatic ductal adenocarcinoma

Abstract

Abstract Perineural invasion (PNI) is frequent in pancreatic ductal adenocarcinoma (PDAC) and contributes to poor prognosis, yet stromal–neural mechanisms remain unclear. We developed a vertical multi-co-culture model incorporating human PDAC cells, neonatal mouse dorsal root ganglion (DRG) neurons, and human pancreatic stellate cells (PSCs). Migration assays demonstrated markedly greater PDAC cell migration in DRG + PSC than either condition alone. Proteomic profiling of conditioned media identified Secreted Protein Acidic and Rich in Cysteine (SPARC) as a highly enriched factor in the DRG + PSC condition. Public transcriptomic datasets (TCGA, GTEx, scRNA-seq) confirmed SPARC upregulation in PDAC, with predominant expression in fibroblasts and association with poor survival. Immunohistochemistry of 81 resected PDAC specimens in Hamamatsu University School of Medicine revealed stromal-rich SPARC expression significantly correlated with PNI-positive status. Collectively, these findings indicate that stromal SPARC is associated with PNI-related aggressiveness in PDAC. SPARC may serve as a biomarker of unfavorable prognosis and as a candidate stromal factor warranting future functional validation within the tumor-nerve-stromal axis.