A mechanism-based computational model to capture the interconnections among epithelial-mesenchymal transition, cancer stem cells and Notch-Jagged signaling

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dc.citation.firstpage29906
dc.citation.issueNumber52
dc.citation.journalTitleOncotarget
dc.citation.lastpage29920
dc.citation.volumeNumber9
dc.contributor.authorBocci, Federico
dc.contributor.authorJolly, Mohit Kumar
dc.contributor.authorGeorge, Jason Thomas
dc.contributor.authorLevine, Herbert
dc.contributor.authorOnuchic, José Nelson
dc.contributor.orgCenter for Theoretical Biological Physics
dc.date.accessioned2018-09-27T17:33:24Z
dc.date.available2018-09-27T17:33:24Z
dc.date.issued2018
dc.description.abstractEpithelial-mesenchymal transition (EMT) and cancer stem cell (CSCs) formation are two fundamental and well-studied processes contributing to cancer metastasis and tumor relapse. Cells can undergo a partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype or a complete EMT to attain a mesenchymal one. Similarly, cells can reversibly gain or lose 'stemness'. This plasticity in cell states is modulated by signaling pathways such as Notch. However, the interconnections among the cell states enabled by EMT, CSCs and Notch signaling remain elusive. Here, we devise a computational model to investigate the coupling among the core decision-making circuits for EMT, CSCs and Notch. Our model predicts that hybrid E/M cells are most likely to associate with stem-like traits and enhanced Notch-Jagged signaling – a pathway implicated in therapeutic resistance. Further, we show that the position of the 'stemness window' on the 'EMT axis' is varied by altering the coupling strength between EMT and CSC circuits, and/or modulating Notch signaling. Finally, we analyze the gene expression profile of CSCs from several cancer types and observe a heterogeneous distribution along the 'EMT axis', suggesting that different subsets of CSCs may exist with varying phenotypes along the epithelial-mesenchymal axis. We further investigate therapeutic perturbations such as treatment with metformin, a drug associated with decreased cancer incidence and increased lifespan of patients. Our mechanism-based model explains how metformin can both inhibit EMT and blunt the aggressive potential of CSCs simultaneously, by driving the cells out of a hybrid E/M stem-like state with enhanced Notch-Jagged signaling.
dc.identifier.citationBocci, Federico, Jolly, Mohit Kumar, George, Jason Thomas, et al.. "A mechanism-based computational model to capture the interconnections among epithelial-mesenchymal transition, cancer stem cells and Notch-Jagged signaling." <i>Oncotarget,</i> 9, no. 52 (2018) Oncotarget: 29906-29920. https://doi.org/10.18632/oncotarget.25692.
dc.identifier.digital25692-1008605-9-PB
dc.identifier.doihttps://doi.org/10.18632/oncotarget.25692
dc.identifier.urihttps://hdl.handle.net/1911/102720
dc.language.isoeng
dc.publisherOncotarget
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/
dc.subject.keywordepithelial-mesenchymal transition (EMT)
dc.subject.keywordcancer stem cells (CSCs)
dc.subject.keywordNotch signaling
dc.subject.keywordhybrid epithelial/mesenchymal (E/M) phenotype
dc.subject.keywordstemness window
dc.titleA mechanism-based computational model to capture the interconnections among epithelial-mesenchymal transition, cancer stem cells and Notch-Jagged signaling
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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