Jia Wen, Jolly Mohit Kumar, Levine Herbert
Center for Theoretical Biological Physics, Northeastern University, Boston, MA, United States.
Department of Physics and Astronomy, Rice University, Houston, TX, United States.
Front Cell Dev Biol. 2022 Jan 17;9:828250. doi: 10.3389/fcell.2021.828250. eCollection 2021.
The epithelial-mesenchymal transition (EMT) is a cellular process critical for wound healing, cancer metastasis and embryonic development. Recent efforts have identified the role of hybrid epithelial/mesenchymal states, having both epithelial and mesehncymal traits, in enabling cancer metastasis and resistance to various therapies. Also, previous work has suggested that NRF2 can act as phenotypic stability factor to help stablize such hybrid states. Here, we incorporate a phenomenological epigenetic feedback effect into our previous computational model for EMT signaling. We show that this type of feedback can stabilize the hybrid state as compared to the fully mesenchymal phenotype if NRF2 can influence SNAIL at an epigenetic level, as this link makes transitions out of hybrid state more difficult. However, epigenetic regulation on other NRF2-related links do not significantly change the EMT dynamics. Finally, we considered possible cell division effects in our epigenetic regulation model, and our results indicate that the degree of epigenetic inheritance does not appear to be a critical factor for the hybrid E/M state stabilizing behavior of NRF2.
上皮-间质转化（EMT）是一个对伤口愈合、癌症转移和胚胎发育至关重要的细胞过程。最近的研究发现，兼具上皮和间质特征的混合上皮/间质状态在促进癌症转移和对各种疗法的抗性方面发挥着作用。此外，先前的研究表明，NRF2可以作为表型稳定性因子来帮助稳定这种混合状态。在此，我们将一种唯象的表观遗传反馈效应纳入我们先前关于EMT信号传导的计算模型中。我们表明，如果NRF2能够在表观遗传水平上影响SNAIL，那么与完全间质表型相比，这种类型的反馈可以稳定混合状态，因为这种联系使得从混合状态转变出来更加困难。然而，对其他与NRF2相关的联系的表观遗传调控并不会显著改变EMT动态。最后，我们在表观遗传调控模型中考虑了可能的细胞分裂效应，我们的结果表明，表观遗传遗传程度似乎不是NRF2混合E/M状态稳定行为的关键因素。
