ABSTRACT: 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.
