Regulation of epithelial-mesenchymal plasticity in pancreatic ductal adenocarcinoma: Role of key molecules in tumor differentiation and therapy

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers, with most patients diagnosed at advanced stages. Therefore, understanding tumor development and improving treatment strategies is critical. Tumor cell plasticity enables differentiation, de-differentiation, and trans-differentiation, processes regulated by EMT and MET. These transitions are often controlled by structurally similar but functionally opposing protein pairs, including alternatively spliced isoforms (RAC1/RAC1B or TAp73α/TAp73β), phosphorylated vs. unphosphorylated forms of the same protein (SMAD3), or ligand source (paracrine vs. autocrine TGF-β1). These proteins modulate canonical and non-canonical TGF-β signaling or function as its effectors. This review explores their roles in epithelial signaling and differentiation, aiming to inform novel targeted and personalized PDAC therapies.