Epithelial cells in solid tumors are observed to undergo EMT, an abnormal pathological process in which cancer cells acquire a mesenchymal phenotype in response to signals they attain from the malignant microenvironment, particularly from reactive stromal cells [
11]. Likewise, cells obtain migratory capacity, resistance to apoptosis and expression of extracellular matrix components [
12]. These changes generate CSCs, a subset of undifferentiated neoplastic cells that can initiate heterogeneous cancers while triggering tumorigenesis. According to the “Seed and Soil” hypothesis, first proposed by Stephen Paget in 1889, cancer-initiating cells are endowed with higher tumor-forming potential and have the capacity to “reproduce” neoplasms when cells seed distant organs to develop metastases [
13]. In PDAC, cancer initiating cells have been specified as those expressing CD44, CD24 and ESA, forming tumors at a higher frequency, compared to cells that do not express this phenotype [
14]. In recent studies, it was demonstrated that more than 65% of PDAC patient-derived organoids had characteristics of CSC, characterized as CD44+ CD24+ [
15]. The EMT phenomenon has been directly related to cancer stem cell features, since CSCs also express an EMT phenotype in various types of cancer, including PDAC. In an analysis of breast cancer, it was observed that the upregulation of EMT transcriptional factors, such as TWIST or SNAI, made the cells more mesenchymal and elevated the expression of CD44 and CD24 [
15]. It was also proposed that the EMT regulator ZEB1 enforces isoforms of CD44, while CD44s activates the expression of ZEB1. As a result, a self-sustaining expression of ZEB1 and CD44 is achieved, thereby linking EMT with the stem cell properties in PDAC [
16]. Therefore, it can be considered that EMT contributes to pancreatic cancer stem cells’ migratory capacity by maintaining their ability to multiply and participate in the production of progenies in metastasis. Apart from CD44+ CD24+ ESA+ populations of pancreatic cancer stem cells, c-Met (mesenchymal–epithelial transition factor) has also been identified as a potential prognostic factor for PDAC [
17]. c-Met is a receptor tyrosine kinase found on the surface of epithelial cells. In normal circumstances, c-Met and its ligand HGF/SF (hepatocyte growth factor/scatter factor) moderate tissue regeneration, wound healing and the formation of nerves and muscles [
18]. The abnormal activation of c-Met can promote the development and progression of multiple cancers [
19]. For instance, a recent analysis compared the median survival for PDAC patients, revealing 21.65 months of viability for negative c-Met patients and only 9.45 months for positive ones [
20]. In this regard, high c-Met expression is closely associated with poor prognosis in PDAC patients. Several other processes that occur during EMT include activation of transcription factors, such as the key regulators, SNAI1, SNAI2, ZEB, and TWIST factors [
21]. These EMT regulators have been shown to repress the expression of E-cadherin, a key epithelial marker. The downregulation of E-cadherin impedes cellular adhesion and imparts cellular motility, which is correlated with reduced chemotherapeutic drug sensitivity [
22,
23]. Concurrently, the activation of snail proteins upregulates the expression of mesenchymal proteins, such as vimentin [
24]. Vimentin is usually found as the main intermediate filament protein of normal mesenchymal tissue. Vimentin functions to maintain cellular integrity and provides resistance against stress factors, and its expression has been detected in epithelial malignancies, such as gastrointestinal tumors. During EMT, pancreatic cells change expression from keratin- to vimentin-type intermediate filaments and become resistant to programed cell death [
25] (
Figure 1).