In vitro toxicogenomics (TGx) has the potential to replace or supplement animal studies. However, TGx studies often suffer from a limited sample size and cell types. Meanwhile, transcriptomic data have been generated for tens of thousands of compounds using cancer cell lines mainly for drug efficacy screening. Here, we asked the question of whether these types of transcriptomic data can be used to support toxicity assessment. We compared transcriptomic profiles from three cancer lines (HL60, MCF7, and PC3) from the CMap data set with those using primary hepatocytes or in vivo repeated dose studies from the Open TG-GATEs database by using our previously reported pair ranking (PRank) method. We observed an encouraging similarity between HL60 and human primary hepatocytes (PRank score = 0.70), suggesting the two cellular assays could be potentially interchangeable. When the analysis was limited to drug-induced liver injury (DILI)-related compounds or genes, the cancer cell lines exhibited promise in DILI assessment in comparison with conventional TGx systems (i.e., human primary hepatocytes or rat in vivo repeated dose). Also, some toxicity-related pathways, such as PPAR signaling pathways and fatty acid-related pathways, were preserved across various assay systems, indicating the assay transferability is biological process-specific. Furthermore, we established a potential application of transcriptomic profiles of cancer cell lines for studying immune-related biological processes involving some specific cell types. Moreover, if PRank analysis was focused on only landmark genes from L1000 or S1500+, the advantage of cancer cell lines over the TGx studies was limited. In conclusion, repurposing of existing cancer-related transcript profiling data has great potential for toxicity assessment, particularly in predicting DILI.

中文翻译：

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癌细胞系的转录组谱可否用于毒性评估？

体外毒理基因组学（TGx）有可能替代或补充动物研究。但是，TGx研究经常遭受样本量和细胞类型有限的困扰。同时，利用癌细胞系主要用于药物功效筛选的成千上万种化合物的转录组数据已经生成。在这里，我们问了以下问题：是否可以使用这些类型的转录组数据来支持毒性评估。我们比较了来自CMap数据集的三个癌症系（HL60，MCF7和PC3）的转录组谱与使用原代肝细胞的转录组谱或通过开放TG-GATEs数据库进行的体内重复剂量研究（通过使用我们先前报道的配对排名（PRank）方法） 。我们观察到HL60与人类原代肝细胞之间存在令人鼓舞的相似性（PRank分数= 0.70），提示这两种细胞测定法可能是潜在可互换的。当分析仅限于与药物诱导的肝损伤（DILI）相关的化合物或基因时，与常规TGx系统（即人原代肝细胞或大鼠体内重复剂量）相比，癌细胞系在DILI评估中显示出希望。同样，在各种测定系统中保留了一些毒性相关的途径，例如PPAR信号传导途径和脂肪酸相关的途径，这表明测定的可转移性是生物学过程特异性的。此外，我们建立了癌细胞系转录组谱在研究涉及某些特定细胞类型的免疫相关生物学过程中的潜在应用。此外，如果PRank分析只针对L1000或S1500 +的标志性基因，与TGx研究相比，癌细胞系的优势是有限的。总之，重新利用现有的癌症相关转录谱分析数据具有​​巨大的潜力，可用于毒性评估，尤其是在预测DILI方面。