Abstract
The initiation of pancreatic ductal adenocarcinoma (PDA) is linked to activating mutations in KRAS. However, in PDA mouse models, expression of oncogenic mutant KRAS during development gives rise to tumors only after a prolonged latency or following induction of pancreatitis. Here we describe a novel mouse model expressing ataxia telangiectasia group D complementing gene (ATDC, also known as TRIM29 [tripartite motif 29]) that, in the presence of oncogenic KRAS, accelerates pancreatic intraepithelial neoplasia (PanIN) formation and the development of invasive and metastatic cancers. We found that ATDC up-regulates CD44 in mouse and human PanIN lesions via activation of β-catenin signaling, leading to the induction of an epithelial-to-mesenchymal transition (EMT) phenotype characterized by expression of Zeb1 and Snail1. We show that ATDC is up-regulated by oncogenic Kras in a subset of PanIN cells that are capable of invading the surrounding stroma. These results delineate a novel molecular pathway for EMT in pancreatic tumorigenesis, showing that ATDC is a proximal regulator of EMT.
Highlights
Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease often diagnosed in an advanced state when there are little/no effective therapies
We reported that ataxia telangiectasia group D complementing gene (ATDC) is highly expressed in almost 90% of human PDAs, suggesting that it has an oncogenic function in the disease (Logsdon et al 2003)
To assess the impact of ATDC on epithelial-to-mesenchymal transition (EMT), we examined the expression of EMT markers in pancreatic intraepithelial neoplasia (PanIN) lesions or PDA samples obtained from KC and AKC mice at the indicated ages
Summary
Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease often diagnosed in an advanced state when there are little/no effective therapies. In rare patients who present with localized disease on clinical imaging at the time of diagnosis, 70% will die from recurrent disease despite seemingly curative surgical resection (Neoptolemos et al 2004), suggesting that subclinical spread may occur at the earliest stages of PDA (Sakorafas and Sarr 2003). These clinical data are supported by a recent study using lineage tracing in a genetically engineered mouse model (GEMM) of PDA in which lineage-marked pancreatic epithelial cells were found to undergo epithelial–mesenchymal transition (EMT), invade the stroma, and enter the bloodstream when conventional histology only revealed preinvasive pancreatic intraepithelial neoplasia (PanIN) (Rhim et al 2012).
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