Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma

作者：Mazur Pawel K; Einwaechter Henrik; Lee Marcel; Sipos Bence; Nakhai Hassan; Rad Roland; Zimber Strobl Ursula; Strobl Lothar J; Radtke Freddy; Kloeppel Guenter; Schmid Roland M; Siveke Jens T^*

来源：Proceedings of the National Academy of Sciences, 2010, 107(30): 13438-13443.

DOI：10.1073/pnas.1002423107

• genetically engineered mice
• K-Ras
• Myc
• Notch
• pancreatic cancer

Pancreatic cancer is one of the most fatal malignancies lacking effective therapies. Notch signaling is a key regulator of cell fate specification and pancreatic cancer development; however, the role of individual Notch receptors and downstream signaling is largely unknown. Here, we show that Notch2 is predominantly expressed in ductal cells and pancreatic intraepithelial neoplasia (PanIN) lesions. Using genetically engineered mice, we demonstrate the effect of conditional Notch receptor ablation in Kras(G12D)-driven pancreatic carcinogenesis. Deficiency of Notch2 but not Notch1 stops PanIN progression, prolongs survival, and leads to a phenotypical switch toward anaplastic pancreatic cancer with epithelial-mesenchymal transition. By expression profiling, we identified increased Myc signaling regulated by Notch2 during tumor development, placing Notch2 as a central regulator of PanIN progression and malignant transformation. Our study supports the concept of distinctive roles of individual Notch receptors in cancer development.

• 出版日期2010-7-27