Supplementary material from "Numb prevents a complete epithelial–mesenchymal transition by modulating Notch signalling"
Posted on 2017-11-16 - 13:51
Epithelial–mesenchymal transition (EMT) plays key roles during embryonic development, wound healing and cancer metastasis. Cells in a partial EMT or hybrid epithelial/mesenchymal (E/M) phenotype exhibit collective cell migration, forming clusters of circulating tumour cells—the primary drivers of metastasis. Activation of cell–cell signalling pathways such as Notch fosters a partial or complete EMT, yet the mechanisms enabling cluster formation remain poorly understood. Using an integrated computational-experimental approach, we examine the role of Numb—an inhibitor of Notch intercellular signalling—in mediating EMT and clusters formation. We show via an mathematical model that Numb inhibits a full EMT by stabilizing a hybrid E/M phenotype. Consistent with this observation, knockdown of Numb in stable hybrid E/M cells H1975 results in a full EMT, thereby showing that Numb acts as a brake for a full EMT and thus behaves as a ‘phenotypic stability factor' by modulating Notch-driven EMT. By generalizing the mathematical model to a multi-cell level, Numb is predicted to alter the balance of hybrid E/M versus mesenchymal cells in clusters, potentially resulting in a higher tumour-initiation ability. Finally, Numb correlates with a worse survival in multiple independent lung and ovarian cancer datasets, hence confirming its relationship with increased cancer aggressiveness.
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Bocci, Federico; Jolly, Mohit Kumar; C. Tripathi, Satyendra; Aguilar, Mitzi; Hanash, Samir M.; Levine, Herbert; et al. (2017). Supplementary material from "Numb prevents a complete epithelial–mesenchymal transition by modulating Notch signalling". The Royal Society. Collection. https://doi.org/10.6084/m9.figshare.c.3931894.v1
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AUTHORS (7)
FB
Federico Bocci
MJ
Mohit Kumar Jolly
SC
Satyendra C. Tripathi
MA
Mitzi Aguilar
SH
Samir M. Hanash
HL
Herbert Levine
JO
José N. Onuchic