Epithelial to Mesenchymal Transition: Key Regulator of Pancreatic Ductal Adenocarcinoma Progression and Chemoresistance

SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma’s (PDAC) dismal prognosis is associated with its aggressive biological behavior and resistance to chemotherapy. Epithelial to mesenchymal transition (EMT) has been recognized as a key driver of PDAC progression and development of drug resistance. EMT is a transient and reversible process leading to transdifferentiation of epithelial cells into a more mesenchymal phenotype. It is regulated by multiple signaling pathways that control the activity of a transcription factors network. Activation of EMT in pre-invasive stages of PDAC has been accused for early dissemination. Furthermore, it contributes to the development of intratumoral heterogeneity and drug resistance. This review summarizes the available data regarding signaling networks regulating EMT and describes the integral role of EMT in different aspects of PDAC pathogenesis. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, characterized by aggressive biological behavior and a lack of response to currently available chemotherapy. Emerging evidence has identified epithelial to mesenchymal transition (EMT) as a key driver of PDAC progression and a central regulator in the development of drug resistance. EMT is a reversible transdifferentiation process controlled by complex interactions between multiple signaling pathways such as TGFb, Wnt, and Notch, which converge to a network of specific transcription factors. Activation of EMT transcriptional reprogramming converts cancer cells of epithelial differentiation into a more mesenchymal phenotypic state. EMT occurrence in pre-invasive pancreatic lesions has been implicated in early PDAC dissemination. Moreover, cancer cell phenotypic plasticity driven by EMT contributes to intratumoral heterogeneity and drug tolerance and is mechanistically associated with the emergence of cells exhibiting cancer stem cells (CSCs) phenotype. In this review we summarize the available data on the signaling cascades regulating EMT and the molecular isnteractions between pancreatic cancer and stromal cells that activate them. In addition, we provide a link between EMT, tumor progression, and chemoresistance in PDAC.