Pancreatic cancer is a lethal disease, and understanding the biology of this cancer is essential for developing more effective early detection and therapeutic strategies. The Hedgehog (Hh) signaling pathway plays a critical role in developmental patterning. Recent studies have demonstrated the seminal role of Hh signaling in mature organ homeostasis, including the response to tissue injury, and in epithelial neoplasia.The majority of endodermal epithelial cancers, including pancreatic cancers, demonstrate a continued requirement for Hh ligand. Currently, little is known of the distribution of Hh-responsive cells in the mature exocrine pancreas, the requirement for this pathway in pancreatic epithelial regeneration, and most importantly, the role of ectopic Hh signaling in the initiation of pancreatic neoplasia. Misexpression of Hh ligands in the developing pancreas leads transgenic mice to perinatal lethality, precluding long-term study of such pancreas-specific dysregulation. Conditional transgenic mice have been engineered, wherein taxomifen induction of bi-transgenic PDX1-Cre-ER T2; loxP-EGFP-loxP-mShh mice leads to ectopic Hh ligand expression in the exocrine pancreas. In conjunction with Hh reporter (Ptch lacZ/+) mice, this model will be utilized to explore the distribution of Hh responsive cells in the mature exocrine pancreas under conditions of ectopic Hh expression. Secondly, the role of Hh pathway in response to exocrine pancreatic injury and in epithelial regeneration will be explored, and the effects of modulating pathway activity on the outcome of exocrine repair determined using both ectopic overexpression and chemical inhibition of the Hh pathway. Finally, the morphologic consequences and molecular correlates of Hh misexpression on initiation of exocrine pancreatic neoplasia will be determined. Specifically, it will be determined whether Hh misexpression can generate a phenotype of multistep progression of pancreatic cancer that resembles the cognate human condition. ? ?
