SMAD4 and cancer: In normal pancreas cells, the TGF-β/SMAD4 signaling pathway induces a tumor suppressive effect by activation of cell cycle arrest, apoptosis of epithelial cells, and the maintenance of genomic integrity; whereas, in PDACs, due to inactivation or loss of SMAD4, SMAD4-independent TGF-β signaling pathways are triggered, resulting in reduced cell cycle arrest and apoptosis, promotion of epithelial-to-mesenchymal transition and angiogenesis and induction of immune suppression, all of which lead to progression and metastasis of cancer cells [134].