Center for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, India.
Present affiliation: Department of Mathematics and Statistics, Indian Institute of Technology Kanpur, Kanpur, India.
PLoS Comput Biol. 2022 Nov 8;18(11):e1010687. doi: 10.1371/journal.pcbi.1010687. eCollection 2022 Nov.
Epithelial to Mesenchymal Transition (EMT) and its reverse-Mesenchymal to Epithelial Transition (MET) are hallmarks of metastasis. Cancer cells use this reversible cellular programming to switch among Epithelial (E), Mesenchymal (M), and hybrid Epithelial/Mesenchymal (hybrid E/M) state(s) and seed tumors at distant sites. Hybrid E/M cells are often more aggressive and metastatic than the "pure" E and M cells. Thus, identifying mechanisms to inhibit hybrid E/M cells can be promising in curtailing metastasis. While multiple gene regulatory networks (GRNs) based mathematical models for EMT/MET have been developed recently, identifying topological signatures enriching hybrid E/M phenotypes remains to be done. Here, we investigate the dynamics of 13 different GRNs and report an interesting association between "hybridness" and the number of negative/positive feedback loops across the networks. While networks having more negative feedback loops favor hybrid phenotype(s), networks having more positive feedback loops (PFLs) or many HiLoops-specific combinations of PFLs, support terminal (E and M) phenotypes. We also establish a connection between "hybridness" and network-frustration by showing that hybrid phenotypes likely result from non-reinforcing interactions among network nodes (genes) and therefore tend to be more frustrated (less stable). Our analysis, thus, identifies network topology-based signatures that can give rise to, as well as prevent, the emergence of hybrid E/M phenotype in GRNs underlying EMP. Our results can have implications in terms of targeting specific interactions in GRNs as a potent way to restrict switching to the hybrid E/M phenotype(s) to curtail metastasis.
上皮-间充质转化（EMT）及其逆转-间充质上皮转化（MET）是转移的标志。癌细胞利用这种可逆的细胞编程，在上皮（E）、间充质（M）和混合上皮/间充质（hybrid E/M）状态之间切换，并在远处播种肿瘤。混合 E/M 细胞通常比“纯”E 和 M 细胞更具侵袭性和转移性。因此，确定抑制混合 E/M 细胞的机制在遏制转移方面可能具有广阔前景。虽然最近已经开发出了多个基于 EMT/MET 的基因调控网络（GRN）的数学模型，但仍需确定丰富混合 E/M 表型的拓扑特征。在这里，我们研究了 13 个不同的 GRN 的动力学，并报告了“混合性”与网络中负/正反馈环数量之间的有趣关联。虽然具有更多负反馈环的网络有利于混合表型，但具有更多正反馈环（PFL）或许多特定于 HiLoops 的 PFL 组合的网络则支持终末（E 和 M）表型。我们还通过显示混合表型可能是由于网络节点（基因）之间的非增强相互作用而产生的，从而建立了“混合性”与网络挫折之间的联系，因此往往更加挫折（更不稳定）。我们的分析因此确定了基于网络拓扑的特征，可以导致以及防止 EMP 下的 GRN 中出现混合 E/M 表型。我们的研究结果可以在靶向 GRN 中的特定相互作用方面具有意义，因为这是限制向混合 E/M 表型（s）转换以遏制转移的有效方法。
