title: Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma.
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.
authors.affiliation: Second Department of Internal Medicine and Institute of Pathology, Technical University of Munich, 81675 Munich, Germany.
authors.forename: Pawel K
authors.initials: PK
authors.lastname: Mazur
authors.forename: Henrik
authors.initials: H
authors.lastname: Einwächter
authors.forename: Marcel
authors.initials: M
authors.lastname: Lee
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.forename: Hassan
authors.initials: H
authors.lastname: Nakhai
authors.forename: Roland
authors.initials: R
authors.lastname: Rad
authors.forename: Ursula
authors.initials: U
authors.lastname: Zimber-Strobl
authors.forename: Lothar J
authors.initials: LJ
authors.lastname: Strobl
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
authors.forename: Günter
authors.initials: G
authors.lastname: Klöppel
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.forename: Jens T
authors.initials: JT
authors.lastname: Siveke
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D002278:Carcinoma in Situ / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1; D051883:Receptor, Notch2; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)