Notch-Induced Myeloid Reprogramming in Spontaneous Pancreatic Ductal Adenocarcinoma by Dual Genetic Targeting.

Autor:	Cheung PF; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.; German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Neff F; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.; German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Neander C; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.; German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Bazarna A; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.; German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Savvatakis K; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.; German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Liffers ST; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.; German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Althoff K; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.; German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Lee CL; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina., Moding EJ; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina., Kirsch DG; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina., Saur D; German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany.; Medical Department, Klinikum rechts der Isar, Technische Universität München, Munich, Germany., Bazhin AV; Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians University, Munich, Germany.; German Caner Consortium (DKTK), Partner Site Munich, Germany., Trajkovic-Arsic M; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.; German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany., Heikenwalder MF; Division of Chronic Inflammation and Cancer, DKFZ, Heidelberg, Germany., Siveke JT; Division of Solid Tumor Translational Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. j.siveke@dkfz.de.; German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany.; Medical Department, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2018 Sep 01; Vol. 78 (17), pp. 4997-5010. Date of Electronic Publication: 2018 May 29.
DOI:	10.1158/0008-5472.CAN-18-0052
Abstrakt:	Despite advances in our understanding of the genetics of pancreatic ductal adenocarcinoma (PDAC), the efficacy of therapeutic regimens targeting aberrant signaling pathways remains highly limited. Therapeutic strategies are greatly hampered by the extensive desmoplasia that comprises heterogeneous cell populations. Notch signaling is a contentious pathway exerting opposite roles in tumorigenesis depending on cellular context. Advanced model systems are needed to gain more insights into complex signaling in the multilayered tumor microenvironment. In this study, we employed a dual recombinase-based in vivo strategy to modulate Notch signaling specifically in myeloid cells to dissect the tumorigenic role of Notch in PDAC stroma. Pancreas-specific KrasG12D activation and loss of Tp53 was induced using a Pdx1-Flp transgene, whereas Notch signaling was genetically targeted using a myeloid-targeting Lyz2-Cre strain for either activation of Notch2-IC or deletion of Rbpj. Myeloid-specific Notch activation significantly decreased tumor infiltration by protumorigenic M2 macrophages in spontaneous endogenous PDAC, which translated into significant survival benefit. Further characterization revealed upregulated antigen presentation and cytotoxic T effector phenotype upon Notch-induced M2 reduction. This approach is the first proof of concept for genetic targeting and reprogramming of myeloid cells in a complex disease model of PDAC and provides evidence for a regulatory role of Notch signaling in intratumoral immune phenotypes. Significance: This study provides insight into the role of myeloid-dependent NOTCH signaling in PDAC and accentuates the need to dissect differential roles of signaling pathways in different cellular components within the tumor microenvironment. Cancer Res; 78(17); 4997-5010. ©2018 AACR . (©2018 American Association for Cancer Research.)
Databáze:	MEDLINE
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