Novel drug resistance- and macrophage polarization-related molecular subtyping and prognostic signature for pancreatic adenocarcinoma

Backgroud: Pancreatic adenocarcinoma (PAAD) is characterized by an aggressive behavior and poor prognosis, requiring innovative therapeutic strategies. Methods: The PAAD datasets were acquired from two publicly available genomic repositories: The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. Drug resistance- and macrophage polarization-related genes (DMRGs) were collected on GeneCards or DRESIS databases. To identify distinct disease subtypes, we identifiedprognostic genes with univarite COX regression analysis, followed by consensus clustering. Then an intersection analysis between differentially expressed genes (DEGs) and a set of DMRGs was performed, and the overlapping genes yielded drug resistance- and macrophage polarization-related differentially expressed genes (DMRDEGs). Based on DMRDEGs identified, a prognostic risk model was constructed. Results: PAAD patients were categorized into two molecularly distinct subgroups, subtype A (1) and subtype B (2), based on DMRGs. Through immunological profiling, we found five distinct immune cell populations with statistically significant variations, notably comprising regulatory T lymphocytes and activated NK cells. Immunological profiling demonstrated that subtype B displayed increased sensitivity to immunotherapy (p < 0.01). A prognostic risk model comprising five key genes ( IL18, EREG, LDHA, SOCS2, and SPP1 ) was built and showed robust predictive capability (area under the curve (AUC) > 0.7). A protein-protein interaction (PPI) network was established focusing on these genes, revealing their function as key regulatory hubs. Conclusion: Our analysis categorized PAAD into two distinct subgroups based on DMRGs and a prognostic risk model developed from these genes exhibits considerable promise for forecasting patient survival outcomes.