Guberman Eric, Sherief Hikmet, Regan Erzsébet Ravasz
Biochemistry and Molecular Biology, The College of Wooster, 1189 Beall Ave, Wooster, OH 44691, USA.
AbbVie Inc, Development Operations, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Comput Struct Biotechnol J. 2020 Aug 4;18:2145-2165. doi: 10.1016/j.csbj.2020.07.016. eCollection 2020.
Epithelial cells respond to their physical neighborhood with mechano-sensitive behaviors required for development and tissue maintenance. These include anchorage dependence, matrix stiffness-dependent proliferation, contact inhibition of proliferation and migration, and collective migration that balances cell crawling with the maintenance of cell junctions. While required for development and tissue repair, these coordinated responses to the microenvironment also contribute to cancer metastasis. Predictive models of the signaling networks that coordinate these behaviors are critical in controlling cell behavior to halt disease. Here we propose a Boolean regulatory network model that synthesizes mechanosensitive signaling that links anchorage to a matrix of varying stiffness and cell density sensing to contact inhibition, proliferation, migration, and apoptosis. Our model can reproduce anchorage dependence and anoikis, detachment-induced cytokinesis errors, the effect of matrix stiffness on proliferation, and contact inhibition of proliferation and migration by two mechanisms that converge on the transcription factor. In addition, we offer testable predictions related to cell cycle-dependent anoikis sensitivity, the molecular requirements for abolishing contact inhibition, and substrate stiffness dependent expression of the catalytic subunit of . Moreover, our model predicts heterogeneity in migratory vs. non-migratory phenotypes in sub-confluent monolayers, and co-inhibition but semi-independent induction of proliferation vs. migration as a function of cell density and mitogenic stimulation. Our model serves as a stepping-stone towards modeling mechanosensitive routes to the epithelial to mesenchymal transition, capturing the effects of the mesenchymal state on anoikis resistance, and understanding the balance between migration versus proliferation at each stage of the epithelial to mesenchymal transition.
上皮细胞通过发育和组织维持所需的机械敏感行为对其物理邻域做出反应。这些行为包括锚定依赖性、基质硬度依赖性增殖、增殖和迁移的接触抑制，以及在维持细胞连接的同时平衡细胞爬行的集体迁移。虽然这些对微环境的协调反应是发育和组织修复所必需的，但它们也促进了癌症转移。协调这些行为的信号网络的预测模型对于控制细胞行为以阻止疾病至关重要。在这里，我们提出了一个布尔调节网络模型，该模型综合了机械敏感信号，该信号将锚定与不同硬度的基质联系起来，并将细胞密度感知与接触抑制、增殖、迁移和细胞凋亡联系起来。我们的模型可以通过两种汇聚于转录因子的机制重现锚定依赖性和失巢凋亡、脱离诱导的胞质分裂错误、基质硬度对增殖的影响以及增殖和迁移的接触抑制。此外，我们提供了与细胞周期依赖性失巢凋亡敏感性、消除接触抑制的分子要求以及催化亚基的底物硬度依赖性表达相关的可测试预测。此外，我们的模型预测了亚汇合单层中迁移与非迁移表型的异质性，以及作为细胞密度和有丝分裂刺激函数的增殖与迁移的共同抑制但半独立诱导。我们的模型是迈向模拟上皮-间质转化的机械敏感途径、捕捉间质状态对失巢凋亡抗性的影响以及理解上皮-间质转化每个阶段迁移与增殖之间平衡的垫脚石。
