Consensus-phenotype integration of transcriptomic and metabolomic data implies a role for metabolism in the chemosensitivity of tumour cells.
Consensus-phenotype integration of transcriptomic and metabolomic data implies a role for metabolism in the chemosensitivity of tumour cells.
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DOI：
10.1371/journal.pcbi.1001113
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发表时间：
2011-03
影响因子：
4.3
通讯作者：
Keun HC
中科院分区：
文献类型：
--
作者：
Cavill R;Kamburov A;Ellis JK;Athersuch TJ;Blagrove MS;Herwig R;Ebbels TM;Keun HC
使用 NCI60 细胞系组的转录组学和代谢组学测量，以及整合分子谱数据的新方法，我们表明与肿瘤细胞对铂类药物化学敏感性相关的生化途径高度一致，即它们描述了一致的表型。在通路分析时直接整合代谢组和转录组数据将共识通路的检测提高了 76%，并揭示了铂敏感性与几种代谢通路之间的关联，而这些关联仅通过转录组分析是无法看出的。这些途径包括 TCA 循环和丙酮酸代谢、脂蛋白摄取和通过挽救途径和从头途径进行的核苷酸合成。将这种方法扩展到广泛的化疗药物中，我们证实了代谢途径与铂敏感性相关的特异性。我们的结论是，代谢表型分析可以在预测铂类化疗的反应中发挥作用，并且分子分析数据的共识表型整合是生物标志物发现和探索生物途径与药物反应之间复杂关系的强大且通用的工具。癌症患者对化疗药物的耐药性非常普遍。我们使用从不同类型癌症中获得的 59 个细胞系，研究了这些细胞中测量的基因和代谢物之间的联系，以及细胞对含铂的常见癌症药物表现出的耐药性。为了结合基因和代谢物提供的信息，我们引入了一种新的基于途径的方法，该方法使我们能够探索不同类型数据之间的协同作用。然后，我们扩展该程序以查看更广泛的药物组，并表明我们发现的与铂相关的途径不仅仅是大量药物经常选择的途径。鉴于在生物学研究中越来越多地使用多组测量（基因、代谢物、蛋白质等），我们展示了一种强大而简单的方法来处理由此产生的大型数据集并整合其知识。我们相信这项工作可能有助于开发一种治疗肿瘤的个性化医学方法，其中测量肿瘤的遗传和代谢变化，然后用于预测最佳治疗方案。
Using transcriptomic and metabolomic measurements from the NCI60 cell line panel, together with a novel approach to integration of molecular profile data, we show that the biochemical pathways associated with tumour cell chemosensitivity to platinum-based drugs are highly coincident, i.e. they describe a consensus phenotype. Direct integration of metabolome and transcriptome data at the point of pathway analysis improved the detection of consensus pathways by 76%, and revealed associations between platinum sensitivity and several metabolic pathways that were not visible from transcriptome analysis alone. These pathways included the TCA cycle and pyruvate metabolism, lipoprotein uptake and nucleotide synthesis by both salvage and de novo pathways. Extending the approach across a wide panel of chemotherapeutics, we confirmed the specificity of the metabolic pathway associations to platinum sensitivity. We conclude that metabolic phenotyping could play a role in predicting response to platinum chemotherapy and that consensus-phenotype integration of molecular profiling data is a powerful and versatile tool for both biomarker discovery and for exploring the complex relationships between biological pathways and drug response. Resistance to chemotherapy drugs in cancer sufferers is very common. Using a panel of 59 cell lines obtained from different types of cancer we study the links between the genes and metabolites measured in these cells and the resistance the cells show to common cancer drugs containing platinum. In order to combine the information given by the genes and metabolites we introduce a new pathway-based approach, which allows us to explore synergy between the different types of data. We then extend the procedure to look at a wider panel of drugs and show that the pathways we found were associated with platinum are not just the pathways which are frequently selected for a large number of drugs. Given the increasing use of multiple sets of measurements (genes, metabolites, proteins etc.) in biological studies, we demonstrate a powerful, yet straightforward method for dealing with the resulting large datasets and integrating their knowledge. We believe that this work could contribute to developing a personalised medicine approach to treating tumours, where the genetic and metabolic changes in the tumour are measured and then used for prediction of the optimal treatment regime.
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影响因子：
4.4
作者：
Craig, Andrew;Sidaway, James;Nicholson, Jeremy
通讯作者：
Nicholson, Jeremy
影响因子：
7.2
作者：
Bylesjo, Max;Eriksson, Daniel;Trygg, Johan
通讯作者：
Trygg, Johan
影响因子：
64.5
作者：
Hsu, Peggy P.;Sabatini, David M.
通讯作者：
Sabatini, David M.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
9.9
作者：
通讯作者：
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