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PMID: 20624967 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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 ·2010-07-27 ·Pages 13438-43

Mazur PK, Einwächter H, Lee M, Sipos B, Nakhai H, Rad R, Zimber-Strobl U, Strobl LJ, Radtke F, Klöppel G, Schmid RM, Siveke JT

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 KrasG12D-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.

MeSH Terms
Adenocarcinoma/genetics,metabolism,pathology Animals Blotting, Western Carcinoma in Situ/genetics,metabolism,pathology Carcinoma, Pancreatic Ductal/genetics,metabolism,pathology Cell Line, Tumor Disease Progression Female Gene Expression Profiling Humans Immunohistochemistry Kaplan-Meier Estimate Male Mice Mice, Knockout Pancreas/metabolism,pathology Pancreatic Neoplasms/genetics,metabolism,pathology Proto-Oncogene Proteins c-myc/genetics,metabolism Proto-Oncogene Proteins p21(ras)/genetics,metabolism Receptor, Notch1/genetics,metabolism Receptor, Notch2/genetics,metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction
Chemicals
Notch1 protein, mouse Notch2 protein, mouse Proto-Oncogene Proteins c-myc Receptor, Notch1 Receptor, Notch2 Hras protein, mouse Proto-Oncogene Proteins p21(ras)
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Mazur Pawel K
Second Department of Internal Medicine and Institute of Pathology, Technical University of Munich, 81675 Munich, Germany.
Einwächter Henrik
Lee Marcel
Sipos Bence
Nakhai Hassan
Rad Roland
Zimber-Strobl Ursula
Strobl Lothar J
Radtke Freddy
Klöppel Günter
Schmid Roland M
Siveke Jens T
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1002423107
Published
2010-07-27
Epub
2010-00-12
Pages
13438-43
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2922150
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.1002423107 PMC Full Text View journal details
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