RNA-Seq Differentiates Tumour and Host mRNA Expression Changes Induced by Treatment of Human Tumour Xenografts with the VEGFR Tyrosine Kinase Inhibitor Cediranib.
RNA-Seq Differentiates Tumour and Host mRNA Expression Changes Induced by Treatment of Human Tumour Xenografts with the VEGFR Tyrosine Kinase Inhibitor Cediranib.
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DOI：
10.1371/journal.pone.0066003
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Barry ST
中科院分区：
文献类型：
--
作者：
Bradford JR;Farren M;Powell SJ;Runswick S;Weston SL;Brown H;Delpuech O;Wappett M;Smith NR;Carr TH;Dry JR;Gibson NJ;Barry ST
肿瘤生物学的临床前模型通常依赖于在小鼠体内繁殖人类肿瘤细胞。为了深入了解这些模型与人类疾病片段的一致性或调查不同治疗方法的效果，尽管存在转录本报道的偏见，以及需要专门的实验方案来分离肿瘤和宿主信号，但经常使用诸如PCR或基于阵列的表达谱等方法。在这里，我们描述了一种使用RNA-Seq的计算策略来分析来自同一RNA样本的临床前异种移植模型的肿瘤和宿主间的转录表达。这一战略的关键是一种特定物种的作图方法，它消除了对RNA种群的操纵、定制的测序方案或物种组成比例的先验知识的需要。该方法表现出与物种特异性RT-qPCR和标准微阵列平台相当的性能，并使我们能够量化头孢拉尼治疗后肿瘤和宿主组织中的基因表达变化，头孢拉尼是一种有效的血管内皮生长因子受体酪氨酸激酶抑制剂，包括减少与内皮或血管相关的多个小鼠转录本，以及增加与头孢拉尼反应的炎症反应相关的基因。在人体内，我们观察到缺氧基因的强烈诱导和细胞周期相关转录本的减少。总之，这项研究确立了RNA-Seq可以应用于临床前模型，以更深入地了解模型特征和复合作用机制，并识别肿瘤和宿主生物标记物。
Pre-clinical models of tumour biology often rely on propagating human tumour cells in a mouse. In order to gain insight into the alignment of these models to human disease segments or investigate the effects of different therapeutics, approaches such as PCR or array based expression profiling are often employed despite suffering from biased transcript coverage, and a requirement for specialist experimental protocols to separate tumour and host signals. Here, we describe a computational strategy to profile transcript expression in both the tumour and host compartments of pre-clinical xenograft models from the same RNA sample using RNA-Seq. Key to this strategy is a species-specific mapping approach that removes the need for manipulation of the RNA population, customised sequencing protocols, or prior knowledge of the species component ratio. The method demonstrates comparable performance to species-specific RT-qPCR and a standard microarray platform, and allowed us to quantify gene expression changes in both the tumour and host tissue following treatment with cediranib, a potent vascular endothelial growth factor receptor tyrosine kinase inhibitor, including the reduction of multiple murine transcripts associated with endothelium or vessels, and an increase in genes associated with the inflammatory response in response to cediranib. In the human compartment, we observed a robust induction of hypoxia genes and a reduction in cell cycle associated transcripts. In conclusion, the study establishes that RNA-Seq can be applied to pre-clinical models to gain deeper understanding of model characteristics and compound mechanism of action, and to identify both tumour and host biomarkers.
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影响因子：
12.3
作者：
Creighton C;Kuick R;Misek DE;Rickman DS;Brichory FM;Rouillard JM;Omenn GS;Hanash S
通讯作者：
Hanash S
影响因子：
64.5
作者：
Acharyya S;Oskarsson T;Vanharanta S;Malladi S;Kim J;Morris PG;Manova-Todorova K;Leversha M;Hogg N;Seshan VE;Norton L;Brogi E;Massagué J
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Massagué J
影响因子：
15.9
作者：
Cascone, Tina;Herynk, Matthew H.;Heymach, John V.
通讯作者：
Heymach, John V.
影响因子：
4
作者：
Harrell, Joshua Chuck;Dye, Wendy W.;Horwitz, Kathryn B.
通讯作者：
Horwitz, Kathryn B.
影响因子：
48
作者：
Pepke, Shirley;Wold, Barbara;Mortazavi, Ali
通讯作者：
Mortazavi, Ali