Mapping the Proteomic Landscape of Pancreatic Cancer: Prognostic Insights and Subtype Stratification.

Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy that lacks reliable biomarkers to guide treatment decisions. Effective prognostic tools are needed to improve its clinical management. We conducted a comprehensive proteomic analysis on 115 PDA patient samples with matched adjacent normal tissue. Differential abundance and pathway analyses identified upregulated proteins and pathways within key subgroups. Unsupervised consensus clustering was used to establish a proteomic-based classification of PDA subtypes. A protein-based risk score was developed and validated using multicox regression analyses with LASSO regularization. A 20-protein diagnostic panel was identified (LGALS1, ANXA2, LGALS3BP, CTSD, S100P, COL12A1, SFN, THBS2, CTHRC1, THBS1, SERPINB5, LAMC2, POSTN, CEACAM6, CTSE, PLEC, PKM, S100A11, TAGLN2, ALDOA). Consensus clustering analysis identified four prognostic proteomic subtypes. Subtypes with poorer prognoses exhibited upregulation of neutrophil degranulation, extracellular matrix remodeling, focal adhesion, Mesenchymal Epithelial Transition, collagen formation, and PI3K-Akt-mTOR-related pathways, indicating a predominance of basal-like and activated stromal features. In tumors with Homologous Recombination Deficiency or COSMIC Signature-3, several immune-related proteins were enriched. An 18-protein (PURB, SDCBP2, CD2BP2, GALM, SERPINA3, OAS3, FAN1, ZPR1, KRT2, NUDT2, SMNDC1, SERPINA4, CUTA, WDR36, POSTN, CLEC11A, PEX14, and PI4KA) risk score demonstrated independent prognostic significance for overall survival, and recurrence, and was validated in an independent proteomic dataset generated using a different proteomic technology. This study introduces four novel prognostic PDA subtypes and an 18-protein risk score, validated in an independent dataset, which show promise for improving survival prediction and could serve as a valuable tool for personalized treatment guidance.