title: Jagged mediates differences in normal and tumor angiogenesis by affecting tip-stalk fate decision.
abstract: Angiogenesis is critical during development, wound repair, and cancer progression. During angiogenesis, some endothelial cells adopt a tip phenotype to lead the formation of new branching vessels; the trailing stalk cells proliferate to develop the vessel. Notch and VEGF signaling mediate the selection of these tip endothelial cells. However, how Jagged, a Notch ligand that is overexpressed in cancer, affects angiogenesis remains elusive. Here, by developing a theoretical framework for Notch-Delta-Jagged-VEGF signaling, we found that higher production levels of Jagged destabilizes the tip and stalk cell fates and can give rise to a hybrid tip/stalk phenotype that leads to poorly perfused and chaotic angiogenesis, which is a hallmark of cancer. Consistently, the signaling interactions that restrict Notch-Jagged signaling, such as Fringe, cis-inhibition, and increased production of Delta, stabilize tip and stalk fates and limit the existence of hybrid tip/stalk phenotype. Our results underline how overexpression of Jagged can transform physiological angiogenesis into pathological one.
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005; Institute of Physics, University of Sao Paulo, Sao Paulo 05508, Brazil;
authors.forename: Marcelo
authors.initials: M
authors.lastname: Boareto
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005; Department of Bioengineering, Rice University, Houston, TX 77005;
authors.forename: Mohit Kumar
authors.initials: MK
authors.lastname: Jolly
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005; School of Physics and Astronomy, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Eshel
authors.initials: E
authors.lastname: Ben-Jacob
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005; jonuchic@rice.edu.
authors.forename: José N
authors.initials: JN
authors.lastname: Onuchic
mesh_terms: D002135:Calcium-Binding Proteins / Q000378:metabolism*; D019070:Cell Lineage / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051880:Receptors, Notch / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D042461:Vascular Endothelial Growth Factor A
keywords: Jagged; Notch signaling; VEGF signaling; angiogenesis; tumor angiogenesis