| Autor: |
Chiblak S; 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., Steinbauer B; Tumor Models, Deutsches Krebsforschungszentrum (DKFZ),69120 Heidelberg, Germany., Pohl-Arnold A; Tumor Models, Deutsches Krebsforschungszentrum (DKFZ),69120 Heidelberg, Germany., Kucher D; Tumor Models, Deutsches Krebsforschungszentrum (DKFZ),69120 Heidelberg, Germany., Abdollahi A; 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., Schwager C; 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., Höft B; Birgit Höft, Division of Cancer Epidemiology, DKFZ, 69120 Heidelberg, Germany., Esposito I; Institute of Pathology, Heinrich-Heine-University of Duesseldorf, 40225 Duesseldorf, Germany., Müller-Decker K; Tumor Models, Deutsches Krebsforschungszentrum (DKFZ),69120 Heidelberg, Germany. |
| Abstrakt: |
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. |
