Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high rate of metastasis. Recent studies have indicated that the Notch signalling pathway is important in PDAC initiation and maintenance, although the specific cell biological roles of the pathway remain to be established. Here we sought to examine this question in established pancreatic cancer cell lines using the γ-secretase inhibitor IX (GSI IX) to inactivate Notch. Based on the known roles of Notch in development and stem cell biology, we focused on effects on epithelial mesenchymal transition (EMT) and on pancreatic tumor initiating CD44+/EpCAM+ cells. We analyzed the effect of the GSI IX on growth and epithelial plasticity of human pancreatic cancer cell lines, and on the tumorigenicity of pancreatic tumor initiating CD44+/EpCAM+ cells. Notably, apoptosis was induced after GSI IX treatment and EMT markers were selectively targeted. Furthermore, under GSI IX treatment, decline in the growth of pancreatic tumor initiating CD44+/EpCAM+ cells was observed in vitro and in a xenograft mouse model. This study demonstrates a central role of Notch signalling pathway in pancreatic cancer pathogenesis and identifies an effective approach to inhibit selectively EMT and suppress tumorigenesis by eliminating pancreatic tumor initiating CD44+/EpCAM+ cells.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of mortality and morbidity with 5-year survival rate of 6% in Europe and the US [1]
Our work reveals that the GSI can selectively block epithelial-mesenchymal transition (EMT), migration and invasion in human pancreatic cancer cell lines, and can suppress pancreatic tumor initiating CD44+/ EpCAM+ cells in a xenograft mouse model.These findings support the development of therapeutic strategies targeting Notch signalling in pancreatic cancer
We found that GSI IX treatment induced significant levels of apoptosis in these pancreatic cancer cell lines, with levels increasing with drug dose (Fig. S3A–B)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of mortality and morbidity with 5-year survival rate of 6% in Europe and the US [1]. Though a number of molecular markers are associated with poor outcomes in pancreatic cancer, one of the important factors contributing for this malignancy is loss of epithelial differentiation. This is manifested as epithelial mesenchymal transition (EMT), which is characterized by the gain of stem cell properties, which promotes cancer invasion and metastasis [10,11]. The hallmark of EMT is the loss of the homotypic adhesion molecule epithelial cadherin (E-cadherin) and gain of mesenchymal markers. In addition to the loss of E-cadherin, the induction of N-cadherin itself might contribute directly to cancer metastasis [11]
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