Boareto Marcelo, Jolly Mohit Kumar, Goldman Aaron, Pietilä Mika, Mani Sendurai A, Sengupta Shiladitya, Ben-Jacob Eshel, Levine Herbert, Onuchic Jose' N
Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA Institute of Physics, University of Sao Paulo, Sao Paulo 05508, Brazil.
Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA Department of Bioengineering, Rice University, Houston, TX 77005-1827, USA.
J R Soc Interface. 2016 May;13(118). 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.
转移可能涉及上皮-间质转化（EMT）及其逆向间质-上皮转化的反复循环。细胞也可以经历部分转化以获得混合上皮/间质（E/M）表型，这种表型允许黏附细胞迁移形成循环肿瘤细胞簇。与经历完全EMT的细胞（间质细胞）相比，这些细胞簇可能具有抗凋亡能力且转移倾向增加。因此，确定能够调节此类细胞簇形成和维持的关键因素可能为抗转移策略提供依据。在这里，我们设计了一个基于机制的理论模型，该模型将通过Notch-Delta-Jagged信号传导的细胞间通讯与EMT的调节联系起来。我们证明，虽然Notch-Delta信号和Notch-Jagged信号都可以在一群细胞中诱导EMT，但只有以Jagged为主导的Notch信号，而不是以Delta为主导的信号，能够导致含有混合E/M细胞的细胞簇的形成。我们的结果为Jagged在肿瘤进展中的作用提供了可能的机制性见解，并提供了一个框架来研究转移过程中其他微环境信号的影响。
