Pancreatic cancer has a devastating prognosis due to 80-90% of diagnostic cases occurring when metastasis has already presented. Activation of the epithelial-mesenchymal transition (EMT) is a prerequisite for metastasis because it allows for the dissemination of tumor cells to blood stream and secondary organs. Here, we sought to determine the role of SET oncoprotein, an endogenous inhibitor of PP2A, in EMT and pancreatic tumor progression. Among the two major isoforms of SET (isoform 1 and isoform 2), higher protein levels of SET isoform 2 were identified in aggressive pancreatic cancer cell lines. Overexpressing SET isoform 2, and to a lesser extent SET isoform 1, in epithelial cell lines promoted EMT-like features by inducing mesenchymal characteristics and promoting cellular proliferation, migration, invasion, and colony formation. Consistently, knockdown of SET isoforms in the mesenchymal cell line partially resisted these characteristics and promoted epithelial features. SET-induced EMT was likely facilitated by increased N-cadherin overexpression, decreased PP2A activity and/or increased expression of key EMT-driving transcription factors. Additionally, SET overexpression activated the Rac1/JNK/c-Jun signaling pathway that induced transcriptional activation of N-cadherin expression. In vivo, SET isoform 2 overexpression significantly correlated with increased N-cadherin in human PDAC and to tumor burden and metastatic ability in an orthotopic mouse tumor model. These findings identify a new role for SET in cancer and have implications for the design and targeting of SET for intervening pancreatic tumor progression.

One of the key reasons for why pancreatic cancer has such a poor prognosis is that >80% of diagnoses occur when metastasis has already presented. At the cellular level, activation of the epithelial‐mesenchymal transition (EMT) is significant because it allows for the dissemination of primary tumor cells to distant sites. In this study, we sought to determine the role of a novel oncoprotein, SET, in EMT and pancreatic cancer cell progression. We found that silencing SET reverted EMT by inducing a cuboidal, epithelial morphology and reducing colony formation, cellular proliferation, migration, and invasion. Consistently, SET overexpression was detected in a subset of pancreatic tumors, especially poorly‐differentiated pancreatic ductal adenocarcinomas. Higher levels of SET protein expression were also identified in all pancreatic cancer cell lines compared with normal human pancreatic ductal epithelial cells. SET‐mediated EMT was determined to be a result of cadherin switching during which the SPARC/Slug and Rac1/JNK/c‐Jun/AP‐1 signaling pathways inhibit epithelial E‐cadherin and promote mesenchymal N‐cadherin, respectively. In brief, we elucidated a novel role for the SET protein in inducing EMT through cadherin switching and revealed the molecular pathways involved. These findings have implications for the design and targeting of pathways necessary for intervening pancreatic tumor progression. Grant Funding Source: Supported by NIH 1021RR571367 and 1021RR571381.