Jia Wen, Tripathi Shubham, Chakraborty Priyanka, Chedere Adithya, Rangarajan Annapoorni, Levine Herbert, Jolly Mohit Kumar
Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.
Department of Physics and Astronomy, Rice University, Houston, TX, USA.
Oncotarget. 2020 Jul 7;11(27):2611-2624. doi: 10.18632/oncotarget.27651.
Epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition (MET) are central to metastatic aggressiveness and therapy resistance in solid tumors. While molecular determinants of both processes have been extensively characterized, the heterogeneity in the response of tumor cells to EMT and MET inducers has come into focus recently, and has been implicated in the failure of anti-cancer therapies. Recent experimental studies have shown that some cells can undergo an irreversible EMT depending on the duration of exposure to EMT-inducing signals. While the irreversibility of MET, or equivalently, resistance to EMT, has not been studied in as much detail, evidence supporting such behavior is slowly emerging. Here, we identify two possible mechanisms that can underlie resistance of cells to undergo EMT: epigenetic feedback in ZEB1/GRHL2 feedback loop and stochastic partitioning of biomolecules during cell division. Identifying the ZEB1/GRHL2 axis as a key determinant of epithelial-mesenchymal plasticity across many cancer types, we use mechanistic mathematical models to show how GRHL2 can be involved in both the abovementioned processes, thus driving an irreversible MET. Our study highlights how an isogenic population may contain subpopulation with varying degrees of susceptibility or resistance to EMT, and proposes a next set of questions for detailed experimental studies characterizing the irreversibility of MET/resistance to EMT.
上皮-间质转化（EMT）及其逆向过程间质-上皮转化（MET）是实体瘤转移侵袭性和治疗抵抗性的核心。虽然这两个过程的分子决定因素已得到广泛表征，但肿瘤细胞对EMT和MET诱导剂反应的异质性最近受到关注，并被认为与抗癌治疗的失败有关。最近的实验研究表明，一些细胞可根据暴露于EMT诱导信号的持续时间经历不可逆的EMT。虽然MET的不可逆性，或者等效地，对EMT的抗性，尚未得到如此详细的研究，但支持这种行为的证据正在慢慢出现。在这里，我们确定了细胞抵抗EMT的两种可能机制：ZEB1/GRHL2反馈回路中的表观遗传反馈和细胞分裂过程中生物分子的随机分配。我们将ZEB1/GRHL2轴确定为多种癌症类型上皮-间质可塑性的关键决定因素，使用机械数学模型展示了GRHL2如何参与上述两个过程，从而驱动不可逆的MET。我们的研究强调了同基因群体可能包含对EMT具有不同程度易感性或抗性的亚群体，并提出了下一组问题，用于详细的实验研究以表征MET的不可逆性/对EMT的抗性。
