Abstract
Metastasis and therapy resistance are main clinical challenges of pancreatic ductal adenocarcinoma (PDAC) still limiting patient`s prognosis. Both are dependent on tumor cell plasticity, which allows rapid adaptation of tumor cells to changing microenvironmental conditions. Epithelial-Mesenchymal-Transition (EMT), a process by which carcinoma cells acquire invasive abilities, is associated with a gain of cancer stem cell (CSC) properties. Different CSC phenotypes were described in PDAC, whereby high levels of the CSC marker Nestin was identified in CSC clones of mesenchymal Panc1 cells, while CSC clones of epithelial Panc89 cells were characterized by a high SOX2 expression. To investigate the functional impact of these CSC markers in PDAC cells with different EMT phenotypes, expression of either CSC marker was silenced in heterogenous (parental) and CSC PDAC populations to analyze their impact on essential malignancy associated properties.SiRNA-mediated knockdown (KD) of NES and/or SOX2 in Panc1 and Panc89 cell variants (parental and CSC population), respectively, was successfully achieved. Decreased NES expression in Panc1 cell variants and decreased SOX2 expression in Panc89 cell variants significantly inhibited self-renewing properties, however, only marginally impacted cell growth, EMT marker expression, migration and invasion properties as well as response to chemotherapy. Overall, our data indicate that Nestin and SOX2 are crucial mediators of self-renewal capabilities of mesenchymal and epithelial PDAC cell variants, respectively, but that further factors are required for the maintenance of other malignancy associated properties.