Multi-omic characterization of MAP4 in pancreatic adenocarcinoma progression: epitranscriptomic networks, EMT Activation, and stromal-immune dynamics

Background Pancreatic adenocarcinoma (PAAD), particularly pancreatic ductal adenocarcinoma (PDAC), is a lethal malignancy with limited therapeutic advancements. Microtubule-associated protein 4 (MAP4), implicated in tumor progression in other cancers, has not been systematically explored in PAAD. This study aims to investigate the role of MAP4 in the progression of PAAD, its association with tumor stemness, signaling pathways, and the tumor microenvironment (TME). Methods MAP4 expression was analyzed in 80 clinical specimens (60 PAAD and 20 normal tissues) using immunofluorescence. Bioinformatics analyses of 179 TCGA-PAAD samples were conducted to assess the prognostic significance of MAP4, its relationship with tumor heterogeneity, stemness, and immune profiles. Functional studies included silencing MAP4 in PAAD cell lines to evaluate effects on proliferation, migration, invasion, and signaling pathway activation, particularly TGF-β and epithelial-mesenchymal transition (EMT) pathways. Results MAP4 was significantly upregulated in PAAD tissues, correlating with poor differentiation ( P  = 0.031) and shorter disease-free ( P  = 4.0e − 4) and progression-free intervals ( P  = 8.5e − 3). MAP4 silencing suppressed proliferation, migration, and invasion ( P  < 0.05). MAP4 strongly correlated with TGF-β signaling ( r  > 0.7), EMT markers (MMP2: r  = 0.61), and RNA modification pathways (m ⁶ A/m ⁵ C/m ¹ A regulators, P  < 0.05). Negative associations with mRNA stemness indices (mRNAsi: r  = − 0.48) suggested stemness modulation via epitranscriptomic networks. TME analysis revealed MAP4’s stromal dominance, with strong cancer-associated fibroblasts (CAFs) correlations (PDGFRB: r  = 0.71; FAP: r  = 0.68) and immunosuppressive features (PD-L1: r  = 0.59; TIDE scores: P  = 0.016). Single-cell data localized MAP4 to fibroblasts and endothelial cells, supporting stromal crosstalk. Conclusions MAP4 drives the progression of PAAD through multiple mechanisms, including the enhancement of TGF-β/EMT signaling, modulation of RNA modification networks to reduce stemness, and promotion of an immunosuppressive TME through CAFs and upregulation of immune checkpoints. These findings highlight the potential of MAP4 as both a prognostic biomarker and a therapeutic target, suggesting opportunities for combined strategies that address both stromal and immune components in treating PAAD.