文章：

卵巢癌中细胞内在的铂类药物反应及其相关的遗传和基因表达特征

Cell-intrinsic platinum response and associated genetic and gene expression signatures in ovarian cancer 

原文发布日期：2025-07-19

英文摘要：

Ovarian cancers are still largely treated with platinum-based chemotherapy as the standard of care, yet few biomarkers of clinical response have had an impact on clinical decision making. Previous work has relied on poor models of the most common subtypes of epithelial ovarian cancers and necessitates a careful examination of the most suitable in vitro models. We performed extensive drug dose response assays and gene expression profiling on 36 ovarian cancer cell lines across over seven subtypes. This is the largest quantitative database of quantitative cisplatin and carboplatin response in ovarian cancer cell lines. Our results demonstrate that cell lines largely fall either well above or below the clinical maximally achievable dose (Cmax) of each compound. We performed differential expression analysis for high-grade serous ovarian carcinoma cell lines. Further, we generated two platinum-resistant derivatives each for OVCAR3 and OVCAR4. Combined with clinically resistant PEO1/PEO4/PEO6 and PEA1/PEA2 isogenic models, we performed differential expression analysis for seven platinum-resistant isogenic pairs. Common themes in differential expression were innate immunity/STAT activation, epithelial-to-mesenchymal transition (EMT) and stemness, and platinum influx/efflux regulators. We also performed copy number signature analysis and orthogonal measures of homologous recombination deficiency (HRD) scar scores and copy number burden, which is the first report to our knowledge applying field-standard copy number signatures to ovarian cancer cell lines. We also examined markers and functional readouts of stemness that revealed that cell lines are poor models for examination of stemness contributions to platinum resistance, suggesting that this is a transient state. Overall, this study serves as a resource to determine the best cell lines to utilize for ovarian cancer research on certain subtypes and platinum response studies, as well as sparks new hypotheses for future study in ovarian cancer. 

摘要翻译：

卵巢癌的治疗仍主要采用以铂类为基础的化疗作为标准方案，但能够影响临床决策的治疗反应生物标志物却极为有限。既往研究多依赖于上皮性卵巢癌最常见亚型的缺陷模型，因此有必要对最合适的体外模型进行严谨评估。本研究对涵盖七个亚型的36种卵巢癌细胞系进行了大规模药物剂量反应检测和基因表达谱分析，构建了目前规模最大的卵巢癌细胞系顺铂/卡铂定量反应数据库。结果表明，细胞系对两种化合物的反应普遍显著高于或低于临床最大可达剂量（Cmax）。我们对高级别浆液性卵巢癌细胞系进行了差异表达分析，并分别构建了OVCAR3和OVCAR4的两种铂类耐药衍生系。结合临床耐药株PEO1/PEO4/PEO6和PEA1/PEA2等同基因模型，我们对七组铂类耐药同基因配对系开展了差异表达分析，发现差异表达的共性主题涉及天然免疫/STAT信号通路激活、上皮-间质转化（EMT）与干性特征、以及铂类药物流入/流出调控机制。我们还进行了拷贝数特征分析，并采用同源重组缺陷（HRD）瘢痕评分和拷贝数负荷作为正交验证——据我们所知，这是首次将领域标准拷贝数特征分析应用于卵巢癌细胞系的研究。针对干性特征的标志物和功能性输出检测表明，现有细胞系模型难以有效研究干性特征对铂类耐药的影响，提示该特性可能处于瞬时状态。总体而言，本研究为特定卵巢癌亚型研究和铂类反应实验提供了细胞系选择的权威参考，并为未来研究方向提供了新的假设思路。

原文链接：

Cell-intrinsic platinum response and associated genetic and gene expression signatures in ovarian cancer