Abstract / Summary
Abstract Pancreatic ductal adenocarcinoma develops through pancreatic intraepithelial neoplasia, but when epithelial–stromal remodeling emerges before invasion remains unclear. Here we integrate spatial transcriptomics, histological validation and patient-derived organoids to characterize isolated human low- and high-grade precursor lesions from pancreata without coexisting invasive carcinoma. High-grade lesions show 3.4-fold periductal stromal expansion, enrichment of myofibroblastic fibroblast programs and elevated stromal interleukin-6. Epithelial basal-like features emerge focally before invasion and expand further in invasive carcinoma organoids. Spatial ligand–receptor analyses identify candidate growth-factor and inflammatory interactions between epithelial and stromal compartments. Conditioned medium from one high-grade precursor-derived organoid line induces both myofibroblastic and inflammatory programs in pancreatic stellate cells, providing proof-of-principle functional support. These findings identify high-grade pancreatic intraepithelial neoplasia as a biologically active preinvasive epithelial–stromal ecosystem and motivate validation of candidate mediators in larger cohorts and perturbation studies.