title: K-Ras and cyclooxygenase-2 coactivation augments intraductal papillary mucinous neoplasm and Notch1 mimicking human pancreas lesions.
abstract: Mutational activation of K-Ras is an initiating event of pancreatic ductal adenocarcinomas (PDAC) that may develop either from pancreatic intraepithelial neoplasia (PanIN) or intraductal papillary mucinous neoplasms (IPMN). Cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) is causally related to pancreatic carcinogenesis. Here, we deciphered the impact of COX-2, a key modulator of inflammation, in concert with active mutant K-Ras(G12D) on tumor burden and gene expression signature using compound mutant mouse lines. Concomitant activation of COX-2 and K-Ras(G12D) accelerated the progression of pancreatic intraepithelial lesions predominantly with a cystic papillary phenotype resembling human IPMN. Transcriptomes derived from laser capture microdissected preneoplastic lesions of single and compound mutants revealed a signature that was significantly enriched in Notch1 signaling components. In vitro, Notch1 signaling was COX-2-dependent. In line with these findings, human IPMN stratified into intestinal, gastric and pancreatobillary types displayed Notch1 immunosignals with high prevalence, especially in the gastric lesions. In conclusion, a yet unknown link between activated Ras, protumorigenic COX-2 and Notch1 in IPMN onset was unraveled.
authors.affiliation: Tumor Models, Deutsches Krebsforschungszentrum (DKFZ),69120 Heidelberg, Germany.|German Cancer Consortium (DKTK); Molecular &Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Heidelberg Institute of Radiation Oncology (HIRO), University of Heidelberg Medical School and National Center for Tumor Diseases (NCT), DKFZ, 69120 Heidelberg, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Chiblak
authors.affiliation: Tumor Models, Deutsches Krebsforschungszentrum (DKFZ),69120 Heidelberg, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Steinbauer
authors.affiliation: Tumor Models, Deutsches Krebsforschungszentrum (DKFZ),69120 Heidelberg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pohl-Arnold
authors.affiliation: Tumor Models, Deutsches Krebsforschungszentrum (DKFZ),69120 Heidelberg, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kucher
authors.affiliation: German Cancer Consortium (DKTK); Molecular &Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Heidelberg Institute of Radiation Oncology (HIRO), University of Heidelberg Medical School and National Center for Tumor Diseases (NCT), DKFZ, 69120 Heidelberg, Germany.
authors.forename: Amir
authors.initials: A
authors.lastname: Abdollahi
authors.affiliation: German Cancer Consortium (DKTK); Molecular &Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Heidelberg Institute of Radiation Oncology (HIRO), University of Heidelberg Medical School and National Center for Tumor Diseases (NCT), DKFZ, 69120 Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schwager
authors.affiliation: Birgit Höft, Division of Cancer Epidemiology, DKFZ, 69120 Heidelberg, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Höft
authors.affiliation: Institute of Pathology, Heinrich-Heine-University of Duesseldorf, 40225 Duesseldorf, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.affiliation: Tumor Models, Deutsches Krebsforschungszentrum (DKFZ),69120 Heidelberg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Müller-Decker
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism*; D002291:Carcinoma, Papillary / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D007249:Inflammation; D051379:Mice; D009154:Mutation; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010641:Phenotype; D015995:Prevalence; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C117307:KRAS protein, human; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D015232:Dinoprostone