Kangsamaksin, ThanedMurtomaki, AinoKofler, Natalie MCuervo, HenarChaudhri, Reyhaan ATattersall, Ian WRosenstiel, Paul EShawber, Carrie JKitajewski, Jan2024-01-172024-01-172015-02Cancer Discov. 2015 Feb;5(2):182-97.http://hdl.handle.net/20.500.12105/17213UNLABELLED A proangiogenic role for Jagged (JAG)-dependent activation of NOTCH signaling in the endothelium has yet to be described. Using proteins that encoded different NOTCH1 EGF-like repeats, we identified unique regions of Delta-like ligand (DLL)-class and JAG-class ligand-receptor interactions, and developed NOTCH decoys that function as ligand-specific NOTCH inhibitors. N110-24 decoy blocked JAG1/JAG2-mediated NOTCH1 signaling, angiogenic sprouting in vitro, and retinal angiogenesis, demonstrating that JAG-dependent NOTCH signal activation promotes angiogenesis. In tumors, N110-24 decoy reduced angiogenic sprouting, vessel perfusion, pericyte coverage, and tumor growth. JAG-NOTCH signaling uniquely inhibited expression of antiangiogenic soluble (s) VEGFR1/sFLT1. N11-13 decoy interfered with DLL1-DLL4-mediated NOTCH1 signaling and caused endothelial hypersprouting in vitro, in retinal angiogenesis, and in tumors. Thus, blockade of JAG- or DLL-mediated NOTCH signaling inhibits angiogenesis by distinct mechanisms. JAG-NOTCH signaling positively regulates angiogenesis by suppressing sVEGFR1-sFLT1 and promoting mural-endothelial cell interactions. Blockade of JAG-class ligands represents a novel, viable therapeutic approach to block tumor angiogenesis and growth. SIGNIFICANCE This is the first report identifying unique regions of the NOTCH1 extracellular domain that interact with JAG-class and DLL-class ligands. Using this knowledge, we developed therapeutic agents that block JAG-dependent NOTCH signaling and demonstrate for the first time that JAG blockade inhibits experimental tumor growth by targeting tumor angiogenesis.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Angiogenesis InhibitorsAnimalsFemaleHumansImmunoglobulin Fc FragmentsAttribution-NonCommercial-NoDerivatives 4.0 Internacional253877665218210.1158/2159-8290.CD-14-06502159-8290Cancer discoveryopen access