Abstract
Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the US. Despite major efforts pancreatic cancer has the highest mortality rate of all major cancers with a 5-year survival rate below 5% while the survival rate for the disease has not improved substantially in nearly 40 years. Recently, doublecortin-like kinase 1 protein (Dclk1) was proposed as a marker of putative quiescent stem cells in the gastrointestinal tract and in the pancreas although no genetic fate mapping was performed. Additionally, it was demonstrated that Dclk1 cells expand in the setting of inflammation, hyperplasia and metaplasia. While clinical relevant mouse models of PDAC exist the identity of the cell of origin for pancreatic cancer is still debated. Aim: In order to investigate the role of Dclk1 cells in pancreatic health and disease we generated a BAC transgenic mouse line (Dclk1-CreERT) that expresses tamoxifen-inducible Cre recombinase under the control of the endogenous Dclk1 gene regulation. Results: Using genetic lineage tracing, we demonstrate that Dclk1 labels rare long-lived, quiescent progenitor cells in the pancreas that can give rise to ductal and acinar tissue. Furthermore, Dclk1 cells were found to expand in the setting of pancreatic inflammation and malignancy. Importantly, the Dclk1 lineage contributed significantly to pancreatic regeneration after caerulein-induced pancreatitis. Finally, expression of mutant K-Ras (G12D) in Dclk-1 cells leads to rapid onset (2-3 months) of invasive pancreatic ductal adenocarcinoma that could be further accelerated by caerulein-induced pancreatic injury (1-2 months). Conclusion: Dclk1 labels rare quiescent progenitor cells in the pancreas. These cells take part in the regeneration of the gland after injury and are capable of giving rise to pancreatic cancer. Therefore, we propose that Dclk1 could label the cell of origin in pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5220. doi:1538-7445.AM2012-5220
Published Version
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