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

Pawel K Mazur; Henrik Einwächter; Marcel Lee; Bence Sipos; Hassan Nakhai; Roland Rad; Ursula Zimber-Strobl; Lothar J Strobl; Freddy Radtke; Günter Klöppel; Roland M Schmid; Jens T Siveke

doi:10.1073/pnas.1002423107

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

Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13438-43. doi: 10.1073/pnas.1002423107. Epub 2010 Jul 12.

Authors

Pawel K Mazur¹, Henrik Einwächter, Marcel Lee, Bence Sipos, Hassan Nakhai, Roland Rad, Ursula Zimber-Strobl, Lothar J Strobl, Freddy Radtke, Günter Klöppel, Roland M Schmid, Jens T Siveke

Affiliation

¹ Second Department of Internal Medicine and Institute of Pathology, Technical University of Munich, 81675 Munich, Germany.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / genetics
Adenocarcinoma / metabolism
Adenocarcinoma / pathology*
Animals
Blotting, Western
Carcinoma in Situ / genetics
Carcinoma in Situ / metabolism
Carcinoma in Situ / pathology*
Carcinoma, Pancreatic Ductal / genetics
Carcinoma, Pancreatic Ductal / metabolism
Carcinoma, Pancreatic Ductal / pathology*
Cell Line, Tumor
Disease Progression
Female
Gene Expression Profiling
Humans
Immunohistochemistry
Kaplan-Meier Estimate
Male
Mice
Mice, Knockout
Pancreas / metabolism
Pancreas / pathology
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology*
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
Proto-Oncogene Proteins p21(ras) / genetics
Proto-Oncogene Proteins p21(ras) / metabolism
Receptor, Notch1 / genetics
Receptor, Notch1 / metabolism
Receptor, Notch2 / genetics
Receptor, Notch2 / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction

Substances

Notch1 protein, mouse
Notch2 protein, mouse
Proto-Oncogene Proteins c-myc
Receptor, Notch1
Receptor, Notch2
Hras protein, mouse
Proto-Oncogene Proteins p21(ras)