Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
PLoS Comput Biol. 2022 Jul 8;18(7):e1010264. doi: 10.1371/journal.pcbi.1010264. eCollection 2022 Jul.
Interindividual variability in DNA damage response (DDR) dynamics may evoke differences in susceptibility to cancer. However, pathway dynamics are often studied in cell lines as alternative to primary cells, disregarding variability. To compare DDR dynamics in the cell line HepG2 with primary human hepatocytes (PHHs), we developed a HepG2-based computational model that describes the dynamics of DDR regulator p53 and targets MDM2, p21 and BTG2. We used this model to generate simulations of virtual PHHs and compared the results to those for PHH donor samples. Correlations between baseline p53 and p21 or BTG2 mRNA expression in the absence and presence of DNA damage for HepG2-derived virtual samples matched the moderately positive correlations observed for 50 PHH donor samples, but not the negative correlations between p53 and its inhibitor MDM2. Model parameter manipulation that affected p53 or MDM2 dynamics was not sufficient to accurately explain the negative correlation between these genes. Thus, extrapolation from HepG2 to PHH can be done for some DDR elements, yet our analysis also reveals a knowledge gap within p53 pathway regulation, which makes such extrapolation inaccurate for the regulator MDM2. This illustrates the relevance of studying pathway dynamics in addition to gene expression comparisons to allow reliable translation of cellular responses from cell lines to primary cells. Overall, with our approach we show that dynamical modeling can be used to improve our understanding of the sources of interindividual variability of pathway dynamics.
个体间 DNA 损伤反应 (DDR) 动力学的变异性可能会导致对癌症易感性的差异。然而，通常在细胞系中研究途径动力学作为替代原发性细胞，而忽略了变异性。为了比较 HepG2 细胞系和原代人肝细胞 (PHH) 中的 DDR 动力学，我们开发了一种基于 HepG2 的计算模型，该模型描述了 DDR 调节剂 p53 及其靶标 MDM2、p21 和 BTG2 的动力学。我们使用该模型生成虚拟 PHH 的模拟，并将结果与 PHH 供体样本的结果进行比较。在没有和存在 DNA 损伤的情况下，HepG2 衍生的虚拟样本中基线 p53 和 p21 或 BTG2 mRNA 表达之间的相关性与 50 个 PHH 供体样本中观察到的中度正相关性相匹配，但与 p53 和其抑制剂 MDM2 之间的负相关性不匹配。影响 p53 或 MDM2 动力学的模型参数操作不足以准确解释这两个基因之间的负相关关系。因此，可以将 HepG2 外推到 PHH 进行一些 DDR 元素，但我们的分析也揭示了 p53 途径调节中的知识差距，这使得该调节剂 MDM2 的外推不准确。这说明了除了基因表达比较之外，研究途径动力学的相关性，以允许从细胞系可靠地转化细胞反应到原代细胞。总的来说，我们的方法表明，动态建模可以用于提高我们对途径动力学个体间变异性来源的理解。
