Comprehensive analysis of NOTCH pathway with tumor environment in pancreatic adenocarcinoma

Abstract Objectives Pancreatic adenocarcinoma (PAAD) ranks among the most prevalent malignant neoplasms, and multiple pathways are involved in its pathogenesis, including the NOTCH pathway. However, the variable biological functions of the pathway in PAAD are controversial. Methods RNA-seq data for PAAD was analyzed using data from The Cancer Genome Atlas and Genotype-Tissue Expression databases. Utilizing Kaplan-Meier survival curves and Cox regression analyses, we examined the prognostic significance. The tumor microenvironment and immunotherapy responses were investigated using ssGSEA, ESTIMATE, and TIDE models. Functional enrichment analysis was used to explore gene functions. Results We identified NOTCH2, JAG1, NOTCH4, and DLL3 as high-priority members of the NOTCH pathway that modulates PAAD. Elevated NOTCH2 and JAG1 levels were markedly linked to reduced overall survival (OS), while increased NOTCH4 and DLL3 levels were significantly related to extended OS. Immune analyses showed that NOTCH-based scores were closely related to the immune microenvironment. NOTCH scores were not only closely correlated with tumor-infiltrating immune cells, but also with immunologically activated and immune checkpoint gene expression. The high NOTCH score group had a higher proportion of tumor-infiltrating immune cells and had better responses to immune checkpoint inhibitor therapy. Conclusions These data indicate that NOTCH2, JAG1, NOTCH4, and DLL3 could function as efficient prognostic biomarkers and therapeutic targets in PAAD, and patients with a high NOTCH score may have a significant response to immune checkpoint inhibitor treatment.