The Role of SMAD4 Inactivation in Epithelial–Mesenchymal Plasticity of Pancreatic Ductal Adenocarcinoma: The Missing Link?

SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma (PDAC) is currently one of the deadliest cancers. Despite the progress that has been made in the research of patient care and the understanding of pancreatic cancer, the survival rate remains mediocre. SMAD4, a tumor-suppressor gene, is specifically inactivated in 50–55% of pancreatic cancers. The role of SMAD4 protein loss in PDAC remains controversial, but seems to be associated with worse overall survival and metastasis. Here, we review the function of SMAD4 inactivation in the context of a specific biological process called epithelial–mesenchymal transition, as it has been increasingly associated with tumor formation, metastasis and resistance to therapy. By improving our understanding of these molecular mechanisms, we hope to find new targets for therapy and improve the care of patients with PDAC. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) presents a five-year survival rate of 10% and its incidence increases over the years. It is, therefore, essential to improve our understanding of the molecular mechanisms that promote metastasis and chemoresistance in PDAC, which are the main causes of death in these patients. SMAD4 is inactivated in 50% of PDACs and its loss has been associated with worse overall survival and metastasis, although some controversy still exists. SMAD4 is the central signal transducer of the transforming growth factor-beta (TGF-beta) pathway, which is notably known to play a role in epithelial–mesenchymal transition (EMT). EMT is a biological process where epithelial cells lose their characteristics to acquire a spindle-cell phenotype and increased motility. EMT has been increasingly studied due to its potential implication in metastasis and therapy resistance. Recently, it has been suggested that cells undergo EMT transition through intermediary states, which is referred to as epithelial–mesenchymal plasticity (EMP). The intermediary states are characterized by enhanced aggressiveness and more efficient metastasis. Therefore, this review aims to summarize and analyze the current knowledge on SMAD4 loss in patients with PDAC and to investigate its potential role in EMP in order to better understand its function in PDAC carcinogenesis.