Molecular mechanisms of meningioma invasion: Function and therapeutic relevance of small GTPases in relation to NF2/Merlin

脑膜瘤侵袭的分子机制：小 GTP 酶与 NF2/Merlin 相关的功能和治疗相关性

• 批准号: 265549829
• 负责人: Professor Dr. Christian Mawrin
• 金额: --
• 依托单位: Institut für Neuropathologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/265549829?language=en
• 关键词: Molecular; mechanisms; meningioma; invasion; Function

Brain-invasive growth of meningioma comprises a highly-relevant clinical problem with negative effects on recurrency rates and overall survival. The knowledge regarding the mechanisms driving meningioma invasion are less-well characterized. The small GTPases RhoA, RAC-1, and cdc42 are important molecules for the regulation of tumor cell motility and -invasion. Few data suggest a role of RAC-1 in aggressive meningiomas, because activating mutations have been found in about 39% of meningiomas in one study. Furthermore, RAc-1 and cdc42 binds to PI3 kinase, which is known to be activated in aggressive/invasive meningiomas. Schwannoma cells with loss of the tumor suppressor NF2/merlin show increased activity of RAC-1 and cdc42. About 50 percent of sporadic human meningiomas are characterized by alterations of NF2, and meningeal knockdown of NF2 leads to meningioma formation in mice. It was recently reported that members of the Rho-GTPase signaling pathway are differentially expressed in meningiomas depending on the NF2 condition.In this project, we aim to define the role of RhoA, RAC-1, and cdc42 for the regulation of meningioma cell invasion and motility in relation the NF2/merlin in detail. We will use established cell culture models including syngenic pairs of meningioma cells with stable knockdown of NF2/merlin, as well as xenograft and genetic mouse models to define whether RhoA, RAC-1, or cdc42 are substantially involved in meningioma cell motility and invasion. The genetic meningioma model previously established by Michel Kalamarides (Paris) is based on Cre-mediated local NF2 knockdown and is already used in our laboratory. These mice can be crossed with floxed mice for each of the three GTPases, providing insight into their regulation of NF2-knockout based meningioma growth and brain invasion. To establish a potential therapeutic impact of GTPase signaling manipulation, we will study the Rho kinase (ROCK) inhibitor Fasudil using our well-established meningioma xenograft mouse model. We expect from the results of the project a significant improvement in the understanding of mechanisms driving meningioma cell invasion, especially in relation to NF2/merlin. The preclinical evaluation of specific inhibitors will bridge to new therapeutic options for meningioma patients not eligible for conventional treatment strategies like surgery or irradiation.

脑膜瘤的脑侵袭性生长是一个高度相关的临床问题，对复发率和总体生存率产生负面影响。关于驱动脑膜瘤侵袭的机制的知识还不太清楚。小 GTP 酶 RhoA、RAC-1 和 cdc42 是调节肿瘤细胞运动和侵袭的重要分子。很少有数据表明 RAC-1 在侵袭性脑膜瘤中发挥作用，因为一项研究在约 39% 的脑膜瘤中发现了激活突变。此外，RAc-1 和 cdc42 与 PI3 激酶结合，已知该激酶在侵袭性/侵袭性脑膜瘤中被激活。失去肿瘤抑制因子 NF2/merlin 的神经鞘瘤细胞显示 RAC-1 和 cdc42 活性增加。大约 50% 的散发性人类脑膜瘤以 NF2 改变为特征，脑膜敲除 NF2 会导致小鼠脑膜瘤形成。最近有报道称，根据 NF2 状况，Rho-GTPase 信号通路成员在脑膜瘤中存在差异表达。在本项目中，我们旨在详细定义 RhoA、RAC-1 和 cdc42 在调节与 NF2/merlin 相关的脑膜瘤细胞侵袭和运动方面的作用。我们将使用已建立的细胞培养模型（包括稳定敲低 NF2/merlin 的同基因对脑膜瘤细胞）以及异种移植和遗传小鼠模型来确定 RhoA、RAC-1 或 cdc42 是否实质上参与脑膜瘤细胞运动和侵袭。 Michel Kalamarides（巴黎）先前建立的遗传性脑膜瘤模型基于 Cre 介导的局部 NF2 敲除，并且已在我们的实验室中使用。这些小鼠可以与具有三种 GTP 酶的 floxed 小鼠杂交，从而深入了解它们对基于 NF2 敲除的脑膜瘤生长和脑侵袭的调节。为了确定 GTPase 信号传导操作的潜在治疗影响，我们将使用我们完善的脑膜瘤异种移植小鼠模型来研究 Rho 激酶 (ROCK) 抑制剂 Fasudil。我们期望该项目的结果能够显着提高对驱动脑膜瘤细胞侵袭机制的理解，特别是与 NF2/merlin 相关的机制。特定抑制剂的临床前评估将为不适合接受手术或放射等传统治疗策略的脑膜瘤患者提供新的治疗选择。