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

作者：Boareto Marcelo; Jolly Mohit Kumar; Goldman Aaron; Pietila Mika; Mani Sendurai A; Sengupta Shiladitya; Ben Jacob Eshel; Levine Herbert^*; Onuchic Jose N^*

来源：Journal of the Royal Society Interface, 2016, 13(118): 20151106.

DOI：10.1098/rsif.2015.1106

• Notch signalling
• epithelial-mesenchymal transition
• circulating tumour cells
• hybrid epithelial/mesenchymal phenotype
• multistability
• cell-cell communication

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.

• 出版日期2016-5-1