Breaking Down the Wall: The Strategic Plan of Cancer to Conquer the Brain.
Breaking Down the Wall: The Strategic Plan of Cancer to Conquer the Brain.
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DOI：
10.1177/1535759720949241
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发表时间：
2020-11
影响因子：
3.6
通讯作者：
M de la Prida L
中科院分区：
文献类型：
--
作者：
Valiente M;M de la Prida L
Hatcher A，Yu K，Meyer J，Aiba I，Deneen B，Noeb JL.《临床投资杂志》2020;130（5）：2286-2300。doi：10.1172/JCI 133316癫痫发作通常预示着神经胶质瘤的临床表现或出现在晚期。剖析它们在脑恶性肿瘤中的精确演变和细胞发病机制可以为这些高度耐药性癫痫的分期治疗的发展提供信息。免疫缺陷异种移植模型的研究已确定局部中间神经元丢失和过量胶质谷氨酸释放是网络去抑制的主要贡献者，但尚不清楚免疫活性大脑中瘤周微环境中的过度兴奋性如何演变。我们通过在子宫内删除关键肿瘤抑制基因在WT小鼠中产生胶质瘤，并在体内电生理学和GCAMP 7钙成像肿瘤浸润期间连续监测皮质癫痫发生，揭示了从过度兴奋到惊厥发作的可重复进展。早在癫痫发作之前，与抑制性细胞及其保护性支架的丧失、神经胶质谷氨酸反向转运体xCT表达的获得和反应性星形胶质细胞增多相一致，我们检测到局部Iba 1+小胶质细胞炎症，其加剧并随后延伸远远超出肿瘤边界。肿瘤周围区域频繁出现的皮质扩散性去极化的早期未识别事件可能为一过性神经功能缺损提供了机制。早期阻断胶质细胞xCT活性抑制了后来的癫痫发作，并且通过删除微管相关蛋白Tau抑制癫痫发生和癫痫发作的分子标记物来降低宿主脑兴奋性的基因组。我们的研究证实了异种移植肿瘤驱动的病理生物学，并揭示了肿瘤相关癫痫发生的早期和晚期成分，在一个遗传上易处理的，免疫活性的胶质瘤小鼠模型，允许肿瘤与宿主致病性癫痫发作机制的复杂解剖。
Pathogenesis of Peritumoral Hyperexcitability in an Immunocompetent CRISPR-Based Glioblastoma Model Hatcher A, Yu K, Meyer J, Aiba I, Deneen B, Noeb JL. J Clin Invest. 2020;130(5):2286-2300. doi:10.1172/JCI133316 Seizures often herald the clinical appearance of gliomas or appear at later stages. Dissecting their precise evolution and cellular pathogenesis in brain malignancies could inform the development of staged therapies for these highly pharmacoresistant epilepsies. Studies in immunodeficient xenograft models have identified local interneuron loss and excess glial glutamate release as chief contributors to network disinhibition, but how hyperexcitability in the peritumoral microenvironment evolves in an immunocompetent brain is unclear. We generated gliomas in WT mice via in utero deletion of key tumor suppressor genes and serially monitored cortical epileptogenesis during tumor infiltration with in vivo electrophysiology and GCAMP7 calcium imaging, revealing a reproducible progression from hyperexcitability to convulsive seizures. Long before seizures, coincident with loss of inhibitory cells and their protective scaffolding, gain of glial glutamate antiporter xCT expression, and reactive astrocytosis, we detected local Iba1+ microglial inflammation that intensified and later extended far beyond tumor boundaries. Hitherto unrecognized episodes of cortical spreading depolarization that arose frequently from the peritumoral region may provide a mechanism for transient neurological deficits. Early blockade of glial xCT activity inhibited later seizures, and genomic reduction of host brain excitability by deleting microtubule-associated protein Tau suppressed molecular markers of epileptogenesis and seizures. Our studies confirmed xenograft tumor–driven pathobiology and revealed early and late components of tumor-related epileptogenesis in a genetically tractable, immunocompetent mouse model of glioma, allowing the complex dissection of tumor versus host pathogenic seizure mechanisms.
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影响因子：
25
作者：
John Lin CC;Yu K;Hatcher A;Huang TW;Lee HK;Carlson J;Weston MC;Chen F;Zhang Y;Zhu W;Mohila CA;Ahmed N;Patel AJ;Arenkiel BR;Noebels JL;Creighton CJ;Deneen B
通讯作者：
Deneen B
影响因子：
3.9
作者：
Sorensen, Mai Froberg;Heimisdottir, Solborg Berglind;Beier, Christoph Patrick
通讯作者：
Beier, Christoph Patrick
影响因子：
64.5
作者：
Venkatesh HS;Johung TB;Caretti V;Noll A;Tang Y;Nagaraja S;Gibson EM;Mount CW;Polepalli J;Mitra SS;Woo PJ;Malenka RC;Vogel H;Bredel M;Mallick P;Monje M
通讯作者：
Monje M
影响因子：
64.5
作者：
Keren-Shaul, Hadas;Spinrad, Amit;Amit, Ido
通讯作者：
Amit, Ido
影响因子：
64.8
作者：
Venkatesh, Humsa S.;Morishita, Wade;Monje, Michelle
通讯作者：
Monje, Michelle