Abstract
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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with no effective therapeutic options for long-term tumor control far
Tumor histology as revealed by Movat's pentachrome stain demonstrated that acinar cells significantly decreased, whereas desmoplasia increased from preneoplasia to advanced stage PDAC (Fig. 1A)
One of the distinctive features of PDAC is that the malignant epithelial cells often account for only a minority of tumor mass, whereas the desmoplastic stroma and other nontumor cells constitute up to 80% [47]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with no effective therapeutic options for long-term tumor control far. Therapeutic targeting of PDAC focusing on deregulated molecular signaling pathways in cancer cells has been largely disappointing. One of the hallmarks of PDAC is the presence of extensive desmoplasia, which comprises heterogeneous cell populations including fibroblasts, immune. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Neff are co-first authors of this article
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call