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A reproducible epithelial transcriptional state combines interferon-associated and secretory programs in pancreatic ductal adenocarcinoma
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DOI：10.3389/fgene.2026.1907806.png)
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Abstract
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Pancreatic ductal adenocarcinoma (PDAC) exhibits extensive epithelial plasticity; yet epithelial states associated with interferon signaling remain incompletely defined. We analyzed cleaned epithelial cells classified as singlets in two independent PDAC single-cell RNA-sequencing cohorts; GSE155698 and GSE212966; and constructed a composite score combining an interferon-associated module (IFNcore) with an epithelial-secretory module (Secretorycore). VM-high cells consistently co-expressed representative genes from both programs. Within individual PDAC tumors; IFNcore and Secretorycore were positively associated in 14 of 17 GSE155698 samples and 5 of 6 GSE212966 samples. Sample-level effect sizes and leave-one-gene-out analyses further identified IRF1; STAT1; and ELF3 as candidate factors associated with distinct components of the state. The principal findings were preserved after doublet filtering and remained detectable in Harmony- and CopyKAT-based robustness analyses. In the independent GSE62452 cohort; the composite score correlated with a non-overlapping interferon signature among 69 PDAC tumors (Spearman rho = 0.584; P = 1.42 × 10^-7). In TCGA-PAAD; a higher continuous score was associated with poorer overall survival in univariate Cox analysis; although the association was attenuated after adjustment for age; sex; stage; and grade. These findings define a reproducible PDAC epithelial transcriptional state in which interferon-associated activity coexists with secretory epithelial identity and nominate IRF1; STAT1; and ELF3 for subsequent functional investigation.
Keywords:
single-cell RNA sequencing
pancreatic ductal adenocarcinoma
interferon signaling
epithelial plasticity
secretory epithelial program
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