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Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma
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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. and Siveke, Jens T.. (2010) Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma. Proceedings of the National Academy of Sciences of the United States of America, Vol.107 (No.30). pp. 13438-13443. ISSN 0027-8424
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Official URL: http://dx.doi.org/10.1073/pnas.1002423107
Abstract
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.
| Item Type: | Journal Article |
|---|---|
| Subjects: | Q Science > QR Microbiology > QR180 Immunology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
| Divisions: | Faculty of Science > Life Sciences (2010- ) > Biological Sciences ( -2010) |
| Library of Congress Subject Headings (LCSH): | Pancreas -- Cancer, Myc oncogenes, Notch genes, Transgenic mice, Tumors -- Growth |
| Journal or Publication Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Publisher: | National Academy of Sciences |
| ISSN: | 0027-8424 |
| Official Date: | 27 July 2010 |
| Volume: | Vol.107 |
| Number: | No.30 |
| Number of Pages: | 6 |
| Page Range: | pp. 13438-13443 |
| Identification Number: | 10.1073/pnas.1002423107 |
| Status: | Peer Reviewed |
| Publication Status: | Published |
| Access rights to Published version: | Restricted or Subscription Access |
| Funder: | German Cancer Aid, German Federal Ministry of Education and Research, Lustgarten Foundation, German Research Foundation [Deutsche Forschungsgemeinschaft] |
| Grant number: | 107195 (GCA), 01GS08115 (GFMER), RFP05-14 & 06-12 (LF), SI 1549/1-1 (GRF) |
| URI: | http://wrap.warwick.ac.uk/id/eprint/5291 |
Data sourced from Thomson Reuters' Web of Knowledge
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