title: Notch-Jagged signalling can give rise to clusters of cells exhibiting a hybrid epithelial/mesenchymal phenotype.
abstract: Metastasis can involve repeated cycles of epithelial-to-mesenchymal transition (EMT) and its reverse mesenchymal-to-epithelial transition. Cells can also undergo partial transitions to attain a hybrid epithelial/mesenchymal (E/M) phenotype that allows the migration of adhering cells to form a cluster of circulating tumour cells. These clusters can be apoptosis-resistant and possess an increased metastatic propensity as compared to the cells that undergo a complete EMT (mesenchymal cells). Hence, identifying the key players that can regulate the formation and maintenance of such clusters may inform anti-metastasis strategies. Here, we devise a mechanism-based theoretical model that links cell-cell communication via Notch-Delta-Jagged signalling with the regulation of EMT. We demonstrate that while both Notch-Delta and Notch-Jagged signalling can induce EMT in a population of cells, only Jagged-dominated Notch signalling, but not Delta-dominated signalling, can lead to the formation of clusters containing hybrid E/M cells. Our results offer possible mechanistic insights into the role of Jagged in tumour progression, and offer a framework to investigate the effects of other microenvironmental signals during metastasis.
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA Institute of Physics, University of Sao Paulo, Sao Paulo 05508, Brazil.
authors.forename: Marcelo
authors.identifier: 0000-0002-9915-6376
authors.initials: M
authors.lastname: Boareto
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA Department of Bioengineering, Rice University, Houston, TX 77005-1827, USA.
authors.forename: Mohit Kumar
authors.initials: MK
authors.lastname: Jolly
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115, USA Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Goldman
authors.affiliation: Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Mika
authors.initials: M
authors.lastname: Pietilä
authors.affiliation: Department of Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA Metastasis Research Center, MD Anderson Cancer Center, Houston, TX 77025, USA.
authors.forename: Sendurai A
authors.initials: SA
authors.lastname: Mani
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115, USA Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA Dana Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Shiladitya
authors.initials: S
authors.lastname: Sengupta
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA School of Physics and Astronomy and The Sagol School of Neuroscience, 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 77005-1827, USA Department of Bioengineering, Rice University, Houston, TX 77005-1827, USA Department of Physics and Astronomy, Rice University, Houston, TX 77005-1827, USA Department of Biosciences, Rice University, Houston, TX 77005-1827, USA herbert.levine@rice.edu.
authors.forename: Herbert
authors.initials: H
authors.lastname: Levine
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA Department of Chemistry, Rice University, Houston, TX 77005-1827, USA Department of Physics and Astronomy, Rice University, Houston, TX 77005-1827, USA Department of Biosciences, Rice University, Houston, TX 77005-1827, USA jonuchic@rice.edu.
authors.forename: Jose' N
authors.initials: JN
authors.lastname: Onuchic
mesh_terms: D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D000072100:Jagged-1 Protein / Q000378:metabolism*; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D009363:Neoplasm Proteins; D051880:Receptors, Notch
keywords: Notch signalling; cell–cell communication; circulating tumour cells; epithelial–mesenchymal transition; hybrid epithelial/mesenchymal phenotype; multistability