A SUZ12-marked epithelial dedifferentiation state with immune co-expression in pancreatic ductal adenocarcinoma.

Polycomb repressive complex 2 (PRC2) silences MHC class I antigen presentation across cancer types, yet the role of its core scaffolding subunit SUZ12 in pancreatic ductal adenocarcinoma (PDAC) immune phenotypes remains poorly characterized. We integrated bulk transcriptomics from three cohorts, scRNA-seq (137,976 cells), mouse spatial transcriptomics (5980 spots), Mendelian randomization, colocalization, DepMap CRISPR dependency, tissue microarray immunofluorescence, and siRNA knockdown. Meta-analysis identified 43 of 45 PcG genes significantly upregulated in PDAC (FDR < 0.05); SUZ12 was consistent across all three cohorts (log2FC = 0.95, FDR = 9.5 ×10^-19). A three-gene classifier (EZH1, RBBP7, RBBP4) achieved AUC = 0.855. Single-cell analysis revealed positive PRC2-MHC-I co-expression in epithelial cells (rho = 0.37), corroborated by mouse spatial transcriptomics (rho = 0.83). SUZ12-high epithelial cells lost acinar identity (PRSS1 log2FC = -6.63) and gained proliferative programs. Prior TMA immunofluorescence showed SUZ12-PD-L1 protein co-expression; siRNA knockdown reduced proliferation and migration. MR for SUZ12 was underpowered (one instrument, non-significant); colocalization returned PP.H4 = 0.023. PHC2 showed a protective association (OR = 0.45, p = 0.010). PcG complex genes are broadly dysregulated in PDAC. SUZ12 upregulation marks an epithelial state characterized by acinar identity loss, proliferative remodeling, and PRC2-MHC-I co-expression, supported by prior protein-level and functional data. Germline genetic analyses were negative or underpowered, and direct mechanistic validation remains needed.