From Extracellular Vesicles-Related Genes to Angiogenesis: KRT7 as a Modulator of the VEGF/VEGFR signaling-dependent angiogenesis in Pancreatic Adenocarcinoma.

Background & Aims: Pancreatic adenocarcinoma (PAAD) is a highly aggressive malignancy with limited treatment options and a poor prognosis. Extracellular vesicles (EVs), which play a central role in intercellular communication, have emerged as promising non-invasive biomarkers for both diagnosis and prognosis. This study aimed to identify EV-related genes, construct a more accurate prognostic model using data from multiple databases, and explore the functional roles of key genes in PAAD. Methods & Results: Four publicly available datasets, PAAD_ExoRbase, TcgaTargetGtex-PAAD, GSE62452_GPL6244, and GSE78229_GPL6244, were analyzed, leading to the identification of 40 differentially expressed EV-related genes. Using the Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression, five prognostic genes, KRT7, KRT19, CXCL5, TNFRSF13C, and GP1BA, were selected to construct a nomogram model for predicting patient outcomes. Single-cell analysis showed that these five genes were expressed in T-proliferative, malignant, and ductal cells. Analyses of immune cell infiltration and immune checkpoints further supported the model's prognostic performance. The regulatory role of the key gene KRT7 was validated in an in-house cohort and confirmed through in vitro experiments and RNA sequencing. Furthermore, analyses of conditioned medium, EV isolation and characterization, and endothelial tube formation assays demonstrated that EVs derived from CFPAC-1 cells carrying KRT7 enhanced PAAD angiogenesis through VEGF/VEGFR signaling.ConclusionA robust prognostic model was established that connects overall survival with immune status in patients with PAAD. This model may offer valuable guidance for tailoring personalized therapies according to patient subtypes. The mechanisms underlying the regulatory role of the key gene KRT7 in this model were further investigated, revealing KRT7 as a pivotal regulator of VEGF/VEGFR signaling-mediated angiogenesis in PAAD.