Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Integr Biol (Camb). 2011 Apr;3(4):408-21. doi: 10.1039/c0ib00092b. Epub 2011 Mar 4.
We introduce an agent-based model of epithelial cell morphogenesis to explore the complex interplay between apoptosis, proliferation, and polarization. By varying the activity levels of these mechanisms we derived phenotypic transition maps of normal and aberrant morphogenesis. These maps identify homeostatic ranges and morphologic stability conditions. The agent-based model was parameterized and validated using novel high-content image analysis of mammary acini morphogenesis in vitro with focus on time-dependent cell densities, proliferation and death rates, as well as acini morphologies. Model simulations reveal apoptosis being necessary and sufficient for initiating lumen formation, but cell polarization being the pivotal mechanism for maintaining physiological epithelium morphology and acini sphericity. Furthermore, simulations highlight that acinus growth arrest in normal acini can be achieved by controlling the fraction of proliferating cells. Interestingly, our simulations reveal a synergism between polarization and apoptosis in enhancing growth arrest. After validating the model with experimental data from a normal human breast line (MCF10A), the system was challenged to predict the growth of MCF10A where AKT-1 was overexpressed, leading to reduced apoptosis. As previously reported, this led to non growth-arrested acini, with very large sizes and partially filled lumen. However, surprisingly, image analysis revealed a much lower nuclear density than observed for normal acini. The growth kinetics indicates that these acini grew faster than the cells comprising it. The in silico model could not replicate this behavior, contradicting the classic paradigm that ductal carcinoma in situ is only the result of high proliferation and low apoptosis. Our simulations suggest that overexpression of AKT-1 must also perturb cell-cell and cell-ECM communication, reminding us that extracellular context can dictate cellular behavior.
我们引入了一个基于代理的上皮细胞形态发生模型，以探索细胞凋亡、增殖和极化之间的复杂相互作用。通过改变这些机制的活性水平，我们推导出了正常和异常形态发生的表型转换图。这些地图确定了稳态范围和形态稳定性条件。基于代理的模型使用新颖的高内涵图像分析进行了参数化和验证，该分析侧重于体外乳腺腺泡形态发生的时间依赖性细胞密度、增殖和死亡率以及腺泡形态。模型模拟表明，细胞凋亡对于启动管腔形成是必要且充分的，但细胞极化是维持生理上皮形态和腺泡球形的关键机制。此外，模拟结果强调，通过控制增殖细胞的比例，可以实现正常腺泡中的腺泡生长停滞。有趣的是，我们的模拟结果显示极化和凋亡之间存在协同作用，可增强生长停滞。在用正常人类乳腺细胞系（MCF10A）的实验数据验证模型后，该系统被要求预测 AKT-1 过表达导致细胞凋亡减少的 MCF10A 的生长情况。如前所述，这导致了非生长停滞的腺泡，其体积非常大，并且部分填充了管腔。然而，令人惊讶的是，图像分析显示核密度比正常腺泡观察到的要低得多。生长动力学表明，这些腺泡的生长速度比组成它们的细胞快。该计算机模型无法复制这种行为，这与原位导管癌仅是高增殖和低凋亡的结果的经典范例相矛盾。我们的模拟结果表明，AKT-1 的过表达也必须扰乱细胞-细胞和细胞-ECM 通讯，提醒我们细胞外环境可以决定细胞行为。
