K-Ras and cyclooxygenase-2 coactivation augments intraductal papillary mucinous neoplasm and Notch1 mimicking human pancreas lesions

• Verfasst von: Chiblak, Sara [VerfasserIn]
• Verfasst von: Steinbauer, Brigitte [VerfasserIn]
• Verfasst von: Pohl-Arnold, Andrea [VerfasserIn]
• Verfasst von: Kucher, Dagmar [VerfasserIn]
• Verfasst von: Abdollahi, Amir [VerfasserIn]
• Verfasst von: Schwager, Christian [VerfasserIn]
• Verfasst von: Höft, Birgit [VerfasserIn]
• Verfasst von: Esposito, Irene [VerfasserIn]
• Verfasst von: Müller-Decker, Karin [VerfasserIn]
• Titel: K-Ras and cyclooxygenase-2 coactivation augments intraductal papillary mucinous neoplasm and Notch1 mimicking human pancreas lesions
• Verf.angabe: Sara Chiblak, Brigitte Steinbauer, Andrea Pohl-Arnold, Dagmar Kucher, Amir Abdollahi, Christian Schwager, Birgit Höft, Irene Esposito & Karin Müller-Decker
• E-Jahr: 2016
• Jahr: 6 July 2016
• Umfang: 13 S.
• Fussnoten: Gesehen am 30.04.2020
• Titel Quelle: Enthalten in: Scientific reports
• Ort Quelle: [London] : Macmillan Publishers Limited, part of Springer Nature, 2011
• Jahr Quelle: 2016
• Band/Heft Quelle: 6(2016) Artikel-Nummer 29455, 13 Seiten
• ISSN Quelle: 2045-2322
• DOI: doi:10.1038/srep29455
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1696960355

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-RasG12D on tumor burden and gene expression signature using compound mutant mouse lines. Concomitant activation of COX-2 and K-RasG12D 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.