Notch-Jagged signalling can give rise to clusters of cells exhibiting a hybrid epithelial/mesenchymal phenotype

J R Soc Interface. 2016 May;13(118):20151106. doi: 10.1098/rsif.2015.1106.


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.

Keywords: Notch signalling; cell–cell communication; circulating tumour cells; epithelial–mesenchymal transition; hybrid epithelial/mesenchymal phenotype; multistability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition*
  • Humans
  • Jagged-1 Protein / metabolism*
  • Models, Biological*
  • Neoplasm Metastasis
  • Neoplasm Proteins / metabolism*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Receptors, Notch / metabolism*
  • Signal Transduction*


  • JAG1 protein, human
  • Jagged-1 Protein
  • Neoplasm Proteins
  • Receptors, Notch