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.

High expression of both desmoplastic stroma and epithelial to mesenchymal transition markers associate with shorter survival in pancreatic ductal adenocarcinoma

“…Our quantitative analysis allowed us to observe that the higher expression of all markers defined a shorter survival for each clinical stage and degree of differentiation, in contrast to other studies in which these markers were individually evaluated in terms of overall survival of patients with PDAC. 44 , 45 , 48 , 65 Some preliminary findings from a semi-quantitative analysis performed in patients with PDAC indicates that EMT markers may be associated with a shorter survival in clinical stages III and IV 40 , 45 and stromal markers could be associated with a shorter survival in clinical stages II; 44 in fact in our cohort of Mexican patients with this subtype of pancreatic cancer this behavior is observed. However, when classifying clinical stages and differentiation grades by subgroups, our study cohort was reduced; hence, further studies should be conducted using an increased sample size.…”

“… 38 Therefore, microenvironment dynamics promotes tumor growth and invasion 29 , 39 and EMT might be helpful as a biomarker in PDAC diagnosis and to be considered as a new therapeutic target in the management of this disease. 40 …”

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

“…A better understanding of the molecular mechanisms underlying PDAC, SMAD4 and EMT could help in the development of effective targeted therapy, which is highly needed in PDAC [ 141 ].…”

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

“…TGF-b, IL-6, IL-1, and Hedgehog are among the most potent and “druggable” inducers of EMT, and a multiplicity of developed inhibitors targeting these pathways are in the process of safety and efficacy evaluation in clinical trials of different phases. Table 4 shows the multiple inhibitors and monoclonal antibodies targeting EMT under clinical trials for PDAC [ 197 ].…”