Inference of Low and High-Grade Glioma Gene Regulatory Networks Delineates the Role of Rnd3 in Establishing Multiple Hallmarks of Cancer.
Inference of Low and High-Grade Glioma Gene Regulatory Networks Delineates the Role of Rnd3 in Establishing Multiple Hallmarks of Cancer.
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DOI：
10.1371/journal.pgen.1005325
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发表时间：
2015-07
期刊：
影响因子：
4.5
通讯作者：
Falciani F
中科院分区：
文献类型：
--
作者：
Clarke K;Daubon T;Turan N;Soulet F;Mohd Zahari M;Ryan KR;Durant S;He S;Herbert J;Ankers J;Heath JK;Bjerkvig R;Bicknell R;Hotchin NA;Bikfalvi A;Falciani F
神经胶质瘤是一组高度异质性的脑肿瘤，难以治疗，高度侵袭性和促血管生成。胶质母细胞瘤患者的平均生存时间不到15个月。了解不同级别胶质瘤的分子基础，从分化良好的低级别肿瘤到高级别肿瘤，是确定新治疗靶点的关键一步。在这里，我们使用数据驱动的方法，从观察数据中学习基因调控网络的结构，并使用由此产生的模型来制定胶质瘤阶段的分子决定因素的假设。值得注意的是，现有知识与代表临床和临床前研究的功能基因组学数据集的整合揭示了控制低级别和高级别胶质瘤的调控回路内的重要特性。我们的分析首先表明，低级别和高级别胶质瘤的特点是两个亚组的Rho GTP酶的活性开关。第一个参与维持正常的神经胶质细胞功能，而第二个与癌症的多个标志的建立有关。接下来，一种新的数据整合方法的开发和应用揭示了RND 3在控制胶质瘤细胞迁移、侵袭、增殖、血管生成和临床结果中的新功能。神经胶质瘤是侵袭性脑肿瘤，具有侵袭性、异质性、难治性，且存活率低。手术切除和化疗可以提高患者的生存率，但最终这种疾病是致命的。胶质瘤存在多个级别，级别越低预后越好。虽然大多数高级别胶质瘤是新生的，但低级别胶质瘤通常进展为更具侵袭性的形式，称为胶质母细胞瘤。在这篇文章中，我们已经表明，通过将先进的网络生物学方法与正确的实验模型相结合，我们能够揭示控制胶质瘤多个标志的新型调控回路。通过分析代表蛋白质-蛋白质相互作用或基因共表达数据的多个网络模型，我们揭示了低级别和高级别胶质瘤之间调节性Rho GTP酶的作用的转换。其中，我们表明RND 3在胶质母细胞瘤中上调，并且是肿瘤增殖，迁移和侵袭的关键调节因子。我们证实RND 3的表达和基因组拷贝数可预测临床结果，这表明这种特定Rho GTd 3活性的变化可能是与转化和肿瘤扩张相关的早期事件。
Gliomas are a highly heterogeneous group of brain tumours that are refractory to treatment, highly invasive and pro-angiogenic. Glioblastoma patients have an average survival time of less than 15 months. Understanding the molecular basis of different grades of glioma, from well differentiated, low-grade tumours to high-grade tumours, is a key step in defining new therapeutic targets. Here we use a data-driven approach to learn the structure of gene regulatory networks from observational data and use the resulting models to formulate hypothesis on the molecular determinants of glioma stage. Remarkably, integration of available knowledge with functional genomics datasets representing clinical and pre-clinical studies reveals important properties within the regulatory circuits controlling low and high-grade glioma. Our analyses first show that low and high-grade gliomas are characterised by a switch in activity of two subsets of Rho GTPases. The first one is involved in maintaining normal glial cell function, while the second is linked to the establishment of multiple hallmarks of cancer. Next, the development and application of a novel data integration methodology reveals novel functions of RND3 in controlling glioma cell migration, invasion, proliferation, angiogenesis and clinical outcome. Gliomas are aggressive brain tumours that are invasive, heterogeneous, refractory to treatment and show poor survival rates. Surgical resection and chemotherapy can increase patient survival but ultimately the disease is fatal. Multiple grades of glioma exist, with lower grades associated to better prognosis. While the majority of high-grade gliomas occur de novo, it is common that low-grade gliomas progress to the more aggressive form known as glioblastoma. In this article, we have shown that by combining advanced network biology approaches with the right experimental models, we are able to reveal novel regulatory circuits controlling multiple hallmarks of glioma. Through analysis of multiple network models representing protein-protein interaction or gene co-expression data we have revealed a switch in the role of regulatory Rho GTPases between low and high-grade gliomas. Amongst these, we show that RND3 is up-regulated in glioblastomas and is a key regulator of tumour proliferation, migration and invasion. We confirm that expression and genomic copy number of RND3 are predictive of clinical outcome, suggesting that changes in the activity of this particular Rho GTPase could be an early event associated to transformation and tumour expansion.
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DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.8
作者：
Chin, CS;Samanta, MP
通讯作者：
Samanta, MP
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：
8
作者：
Baldwin, R. M.;Parolin, D. A. E.;Lorimer, I. A. J.
通讯作者：
Lorimer, I. A. J.
影响因子：
64.8
作者：
Heng, Julian Ik-Tsen;Nguyen, Laurent;Guillemot, Francois
通讯作者：
Guillemot, Francois