Epithelial to Mesenchymal Transition in Patients with Pancreatic Ductal Adenocarcinoma: State-of-the-Art and Therapeutic Opportunities

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the malignancies with the worst prognosis despite a decade of efforts. Up to eighty percent of patients are managed at late stages with metastatic disease, in part due to a lack of diagnosis. The effectiveness of PDAC therapies is challenged by the early and widespread metastasis. Epithelial to mesenchymal transition (EMT) is a major driver of cancer progression and metastasis. This process allows cancer cells to gain invasive properties by switching their phenotype from epithelial to mesenchymal. The importance of EMT has been largely described in PDAC, and its importance is notably highlighted by the two major subtypes found in PDAC: the classical epithelial and the quasi-mesenchymal subtypes. Quasi-mesenchymal subtypes have been associated with a poorer prognosis. EMT has also been associated with resistance to treatments such as chemotherapy and immunotherapy. EMT is associated with several key molecular markers both epithelial and mesenchymal. Those markers might be helpful as a biomarker in PDAC diagnosis. EMT might becoming a key new target of interest for the treatment PDAC. In this review, we describe the role of EMT in PDAC, its contribution in diagnosis, in the orientation and treatment follow-up. We also discuss the putative role of EMT as a new therapeutic target in the management of PDAC.

Keywords: EMT; PDAC; biomarker; metastasis.

Figure 1

Signaling pathway involved in the epithelial to mesenchymal transition. Different signaling pathways can activate epithelial to mesenchymal transition (EMT) through the activation of EMT transcription factors ZEB1, SNAIL, and TWIST. Interleukin 6 (IL-6) and interleukin 1β (IL-1β) can bind cytokine receptors. Signaling is conducted through the activation of Janus kinase (JAK) and the recruitment of signal transducer and activator of transcription proteins (STATs); the dimer of STATs translocates into the nucleus to activate the transcription of genes. The transforming growth factor β (TGF-β) signal is conducted by SMADs protein into the nucleus, and the trimer activates the transcription. Tyrosine kinase receptors (RTK), such as epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), or platelet-derived growth factor receptor (PDGFR), induce PI3K, AKT, and nuclear factor-κB (NF-κB). The TGF-β pathway and RTK are also able to trigger the RAS-RAF-MEK-ERK signaling pathway. The WNT signaling results in the release of β-Catenin from the glycogen synthase kinase-3β (GSK3β)–axis inhibition protein (AXIN) complex. β-Catenin moves into the nucleus and binds to the transcription factors T cell factor (TCF) and the lymphoid enhancer-binding factor (LEF). Intracellular domain of the notch receptor (Notch ICD) is cleaved after the activation of the receptor, then it can translocate into the nucleus and act as a transcriptional co-activator. Hedgehog signaling induces EMT-associated gene expression through the activation of GLI1.

Figure 2

Impact of the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) in the activation of epithelial to mesenchymal transition (EMT). Cancer-associated fibroblasts (CAFs) induce the production of extracellular matrix (ECM) that is composed of fibronectin, hyaluronic acid, collagen, and laminin. This dense desmoplastic stroma limits the diffusion of oxygen in the tumor and leads to hypoxia. CAFs release different cytokines and chemokines including the transforming growth factor β (TGF-β), interleukin 1 (IL-1), interleukin 6 (IL-6), and the tumor necrosis factor α (TNF-α). These extracellular mediators can activate signaling pathways leading to the activation of EMT in which cells switch from their epithelial phenotype to a mesenchymal phenotype with a spindle-shape morphology. EMT is then followed by intravasion of mesenchymal cells, blood stream survival, extravasion, and finally by the formation of metastasis.

Figure 3

Agents in clinical trials targeting ligands or receptors of signaling pathways implied in the activation of epithelial to mesenchymal transition in pancreatic cancer.