Identification of a Druggable Pathway Controlling Glioblastoma Invasiveness
Identification of a Druggable Pathway Controlling Glioblastoma Invasiveness
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DOI：
10.1016/j.celrep.2017.06.036
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发表时间：
2017-07-05
期刊：
影响因子：
8.8
通讯作者：
Bernards, Rene
中科院分区：
文献类型：
--
作者：
Pencheva, Nora;de Gooijer, Mark C.;Bernards, Rene
弥漫性和不可控的脑侵犯是胶质母细胞瘤（GBM）的特征，但其机制尚不清楚。我们建立了一个三维离体器官型模型来研究GBM的侵袭。我们证明，侵袭的GBM细胞上调细胞外基质（ECM）成分网络，包括多种胶原，其表达与分级和临床结果密切相关。我们发现干扰素调节因子3 （IRF3）是ECM因子的转录抑制因子，并表明IRF3是GBM侵袭的抑制因子。通过抑制酪蛋白激酶2 (CK2) （IRF3的负调节因子）的治疗性激活IRF3，在体外和体内模型中下调ECM因子的表达并抑制GBM侵袭，这些模型涉及一组代表主要分子GBM亚型的患者来源的GBM细胞系。我们的数据提供了对GBM肿瘤侵袭能力的机制洞察，并确定了抑制GBM侵袭的潜在治疗方法。
Diffuse and uncontrollable brain invasion is a hallmark of glioblastoma (GBM), but its mechanism is understood poorly. We developed a 3D ex vivo organotypic model to study GBM invasion. We demonstrate that invading GBM cells upregulate a network of extracellular matrix (ECM) components, including multiple collagens, whose expression correlates strongly with grade and clinical outcome. We identify interferon regulatory factor 3 (IRF3) as a transcriptional repressor of ECM factors and show that IRF3 acts as a suppressor of GBM invasion. Therapeutic activation of IRF3 by inhibiting casein kinase 2 (CK2)-a negative regulator of IRF3-downregulated the expression of ECM factors and suppressed GBM invasion in ex vivo and in vivo models across a panel of patient-derived GBM cell lines representative of the main molecular GBM subtypes. Our data provide mechanistic insight into the invasive capacity of GBM tumors and identify a potential therapy to inhibit GBM invasion.