Sullivan Emmalee, Harris Marlayna, Bhatnagar Arnav, Guberman Eric, Zonfa Ian, Ravasz Regan Erzsébet
Biochemistry and Molecular Biology, The College of Wooster, Wooster, OH 44691, USA.
Ohio University Heritage College of Osteopathic Medicine, Cleveland, OH44122, USA.
iScience. 2023 Mar 2;26(4):106321. doi: 10.1016/j.isci.2023.106321. eCollection 2023 Apr 21.
The significance of biophysical modulators of the epithelial to mesenchymal transition (EMT) is demonstrated by experiments that document full EMT on stiff, nano-patterned substrates in the absence of biochemical induction. Yet, current models focus on biochemical triggers of EMT without addressing its mechanosensitive nature. Here, we built a Boolean model of EMT triggered by mechanosensing - mitogen crosstalk. Our model reproduces epithelial, hybrid E/M and mesenchymal phenotypes, the role of autocrine TGFβ signaling in maintaining mesenchymal cells in the absence of external drivers, inhibition of proliferation by TGFβ, and its apoptotic effects on soft ECM. We offer testable predictions on the density-dependence of partial EMT, its molecular drivers, and the conflict between mitosis and hybrid E/M stability. Our model opens the door to modeling the effects of the biomechanical environment on cancer cell stemness linked to the hybrid E/M state, as well as the mutually inhibitory crosstalk between EMT and senescence.
上皮-间质转化（EMT）的生物物理调节因子的重要性通过实验得到了证明，这些实验记录了在没有生化诱导的情况下，在坚硬的纳米图案化底物上发生的完全EMT。然而，目前的模型专注于EMT的生化触发因素，而没有涉及其机械敏感性质。在这里，我们构建了一个由机械传感-丝裂原串扰触发的EMT布尔模型。我们的模型再现了上皮、混合E/M和间质表型，自分泌TGFβ信号在没有外部驱动因素的情况下维持间质细胞的作用，TGFβ对增殖的抑制作用及其对软细胞外基质的凋亡作用。我们对部分EMT的密度依赖性、其分子驱动因素以及有丝分裂与混合E/M稳定性之间的冲突提供了可测试的预测。我们的模型为模拟生物力学环境对与混合E/M状态相关的癌细胞干性的影响，以及EMT与衰老之间的相互抑制串扰打开了大门。
