Notch-Jagged signalling can give rise to clusters of cells exhibiting a hybrid epithelial/mesenchymal phenotype.
Notch-Jagged signalling can give rise to clusters of cells exhibiting a hybrid epithelial/mesenchymal phenotype.
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DOI：
10.1098/rsif.2015.1106
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发表时间：
2016-05
期刊：
影响因子：
--
通讯作者：
Onuchic JN
中科院分区：
文献类型：
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作者：
Boareto M;Jolly MK;Goldman A;Pietilä M;Mani SA;Sengupta S;Ben-Jacob E;Levine H;Onuchic JN
转移可能涉及上皮-间质转化（EMT）及其反向间质-上皮转化的重复循环。细胞还可以经历部分转变以获得混合上皮/间质（E/M）表型，从而允许粘附细胞迁移形成循环肿瘤细胞簇。与经历完整 EMT 的细胞（间充质细胞）相比，这些簇可以抵抗细胞凋亡，并且具有增加的转移倾向。因此，确定能够调节此类簇的形成和维持的关键参与者可能会为抗转移策略提供信息。在这里，我们设计了一种基于机制的理论模型，通过 Notch-Delta-Jagged 信号传导将细胞间通信与 EMT 调节联系起来。我们证明，虽然Notch-Delta和Notch-Jagged信号传导都可以诱导细胞群中的EMT，但只有Jagged主导的Notch信号传导，而不是Delta主导的信号传导，可以导致包含混合E/M细胞的簇的形成。我们的结果为锯齿状在肿瘤进展中的作用提供了可能的机制见解，并提供了研究转移过程中其他微环境信号的影响的框架。
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.