Phenotype-dependent epithelial–mesenchymal plasticity in pancreatic ductal adenocarcinoma and redox modulation by sodium selenite in vitro and ex vivo

Pancreatic ductal adenocarcinoma (PDAC) is lethal and exhibits epithelial–mesenchymal transition (EMT) plasticity linked to invasion and therapy resistance. Selenite is a redox-active compound with tumor-selective cytotoxicity, but its impact on EMT-related phenotypes in PDAC is unclear. We integrated cell-line profiling and patient-derived tissue-slice cultures to quantify selenite-driven EMT modulation using a multiplex protein panel (EpCAM, CK, E-cad, AHNAK2, ITGAV, Vimentin), histologic regression scoring, and paired RNA sequencing. Across three PDAC cell lines (PANC-1, HPAF-II, Capan-2), selenite effects were phenotype-contingent. HPAF-II and Capan-2 showed epithelial reinforcement and increased EM ratio, whereas mesenchymal-like PANC-1 showed limited epithelial restoration and blunted EM-ratio changes. Selenite most consistently suppressed mesenchymal markers, particularly ITGAV and Vimentin. After TGF-β priming, HPAF-II retained an epithelial-promoting response; in Capan-2, this was evident mainly at the higher selenite dose. In ex vivo PDAC tissue slices (n=10), effects were largely confined to tumor region. Tumors showed dose-dependent EpCAM induction and non-linear E-cad and AHNAK2 responses, while acinar compartments remained stable. Tumor EM ratio was higher at 15 µM than at 5 µM, with improved regression by Evans/CAP criteria. In paired RNA-seq, 5 µM produced no significant EMT-gene differential expression, whereas 15 µM upregulated immediate-early/stress-responsive genes and downregulated genes that build and connect the basement membrane and extracellular matrix, the adhesive scaffold supporting EMT, rather than a canonical MET program. Together, these data indicate that selenite is a dose- and context-dependent modulator of complex, phenotype-dependent EMT-related changes in PDAC and support the translational potential of selenite as a therapeutic strategy.