Computational biology and chemistry · 2026
A SUZ12-marked epithelial dedifferentiation state with immune co-expression in pancreatic ductal adenocarcinoma.
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Wang Zhuoxin, Jin Chenyang, Yin Fei, Wu Xuejiao, Yang Zilin
Аннотация
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.