A combination approach of pseudotime analysis and mathematical modeling for understanding drug-resistant mechanisms.
A combination approach of pseudotime analysis and mathematical modeling for understanding drug-resistant mechanisms.
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伪时间分析与数学建模相结合的方法研究耐药机制。
DOI：
10.1038/s41598-021-97887-z
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发表时间：
2021-09-16
影响因子：
4.6
通讯作者：
Okada M
中科院分区：
文献类型：
--
作者：
Magi S;Ki S;Ukai M;Domínguez-Hüttinger E;Naito AT;Suzuki Y;Okada M
癌细胞通过以下阶段获得耐药性：非耐药、预耐药和耐药。尽管耐药的分子机制已经得到了很好的研究，但耐药获得的过程在很大程度上仍然是未知的。在这里，我们通过对他莫昔芬处理的乳腺癌细胞中基因表达模式的连续分析，阐明了耐药性获得过程的分子机制。单细胞RNA测序表明，他莫昔芬耐药细胞可以分为两个亚组，一个显示与代谢调控相关的基因表达改变，另一个显示粘附相关分子和组蛋白修饰酶的高表达水平。伪时间分析表明，细胞过渡轨迹的两个耐药亚组，源于一个共同的前耐药状态。基于该轨迹建立的常微分方程模型与细胞生长的实验结果吻合较好。基于所建立的模型，预测并实验验证了抑制向两种耐药亚型的转变将防止他莫昔芬耐药的出现。
Cancer cells acquire drug resistance through the following stages: nonresistant, pre-resistant, and resistant. Although the molecular mechanism of drug resistance is well investigated, the process of drug resistance acquisition remains largely unknown. Here we elucidate the molecular mechanisms underlying the process of drug resistance acquisition by sequential analysis of gene expression patterns in tamoxifen-treated breast cancer cells. Single-cell RNA-sequencing indicates that tamoxifen-resistant cells can be subgrouped into two, one showing altered gene expression related to metabolic regulation and another showing high expression levels of adhesion-related molecules and histone-modifying enzymes. Pseudotime analysis showed a cell transition trajectory to the two resistant subgroups that stem from a shared pre-resistant state. An ordinary differential equation model based on the trajectory fitted well with the experimental results of cell growth. Based on the established model, it was predicted and experimentally validated that inhibition of transition to both resistant subtypes would prevent the appearance of tamoxifen resistance.
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