Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 30, Pages 13438-13443Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1002423107
Keywords
genetically engineered mice; K-Ras; Myc; Notch; pancreatic cancer
Categories
Funding
- German Cancer Aid [107195]
- German Federal Ministry of Education and Research [01GS08115]
- Lustgarten Foundation [RFP05-14, 06-12]
- German Research Foundation [SI 1549/1-1]
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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.
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