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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. doi:10.1073/pnas.1002423107

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Official URL: http://dx.doi.org/10.1073/pnas.1002423107

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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
Dates:
DateEvent
27 July 2010Published
Volume: Vol.107
Number: No.30
Number of Pages: 6
Page Range: pp. 13438-13443
DOI: 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)

Data sourced from Thomson Reuters' Web of Knowledge

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