Deciphering the molecular crosstalk between pancreatic ductal adenocarcinoma and type 2 diabetes through...

Pancreatic ductal adenocarcinoma (PDAC) has become the third most common cause of cancer-related deaths worldwide, and its incidence is steadily increasing. Notably, many patients with PDAC develop type 2 diabetes mellitus (T2DM) months or even years prior to cancer diagnosis. This study employed weighted gene co-expression network analysis (WGCNA) to identify shared genes between PDAC and T2DM that may contribute to the pathogenesis and progression of PDAC.

WGCNA was applied to screen for genes at the intersection of PDAC-related apoptotic and necrotic pathways and differentially expressed genes (DEGs) in T2DM. A weighted gene co-expression network was developed using genes with the greatest variance. Multiple analytical approaches were then used to further characterize key genes, including functional enrichment analysis, random survival forest analysis, immune cell infiltration profiling, regulatory network analysis, drug sensitivity prediction, gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), nomogram development, and single-cell RNA sequencing analysis.

Seventeen genes were identified as commonly expressed in both conditions and were enriched in apoptosis-related pathways, suggesting shared molecular mechanisms. Among them, GBP2 and LY6E emerged as central hub genes in both the test and validation cohorts. Further analysis revealed that GBP2 was positively associated with parainflammation and major histocompatibility complex (MHC) class I expression, while LY6E was correlated with type I interferon response and parainflammation, indicating their significant roles in immune cell recruitment and the tumor immune microenvironment. Regulatory network analysis showed that both genes were influenced by common transcription factors, and drug sensitivity analysis, using Genomics of Drug Sensitivity in Cancer data, suggested potential correlations between gene expression and chemotherapy response. GSEA revealed that GBP2 was enriched in B cell receptor and tumor necrosis factor (TNF) signaling pathways, while LY6E was related to interleukin (IL)-17 and nucleotide-binding oligomerization domain (NOD)-like receptor signaling pathways. A prognostic nomogram incorporating GBP2 and LY6E expression demonstrated strong predictive performance for overall survival (OS) in PDAC patients.

In conclusion, GBP2 and LY6E are promising biomarkers for the early detection of PDAC in patients with T2DM. Their involvement in immune modulation and drug sensitivity highlights their potential as therapeutic targets, shedding light on both the pathogenesis and clinical management of PDAC.