Integrative Single-Cell and Spatial Transcriptomics Analysis Reveals ECM-remodeling Cancer-associated Fibroblast-Derived POSTN as a Key Mediator in Pancreatic Ductal Adenocarcinoma Progression

Pancreatic ductal adenocarcinoma (PDAC) presents significant clinical challenges owing to its dense stroma and complex tumor microenvironment (TME). In this study, large-scale single-cell transcriptomics and spatial transcriptomics (ST) were integrated to dissect the heterogeneity of fibroblasts and their crosstalk with epithelial cells, with a focus on key ligand-receptor interactions. Eight distinct fibroblast subpopulations were identified, among which extracellular matrix (ECM)-remodeling fibroblasts were particularly enriched in tumor tissues and associated with poor prognosis. ECM-remodeling fibroblasts were located at the terminal stage of the fibroblast pseudotime trajectory, and SOX11 was identified as a key transcription factor in this subpopulation. Further analyses revealed that ECM-remodeling fibroblasts can interact with epithelial cells through the POSTN-ITGAV/ITGB5 ligand-receptor axis, a critical pathway that promotes tumor progression. Clinical analyses demonstrated a strong correlation between POSTN expression and poor prognosis in patients with PDAC. Mechanistically, POSTN interacts with integrin ITGAV/ITGB5 on tumor cells, activating the PI3K/AKT/β-catenin pathway and promoting epithelial-mesenchymal transition (EMT) phenotype. Pharmacological inhibition of the POSTN-integrin axis partially reversed these malignant traits, highlighting its potential as a therapeutic target. This study provides new insights into fibroblast heterogeneity and its role in PDAC progression, emphasizing the POSTN-ITGAV/ITGB5 axis as a promising target for therapeutic interventions.