Glucose transporter Glut1 controls diffuse invasion phenotype with perineuronal satellitosis in diffuse glioma microenvironment.
Glucose transporter Glut1 controls diffuse invasion phenotype with perineuronal satellitosis in diffuse glioma microenvironment.
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DOI：
10.1093/noajnl/vdaa150
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发表时间：
2021-01
期刊：
影响因子：
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通讯作者：
Tomita H
中科院分区：
文献类型：
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作者：
Miyai M;Kanayama T;Hyodo F;Kinoshita T;Ishihara T;Okada H;Suzuki H;Takashima S;Wu Z;Hatano Y;Egashira Y;Enomoto Y;Nakayama N;Soeda A;Yano H;Hirata A;Niwa M;Sugie S;Mori T;Maekawa Y;Iwama T;Matsuo M;Hara A;Tomita H
神经胶质瘤通常逃脱手术切除并由于其“弥漫性侵袭”表型而复发，使其能够弥漫性浸润到正常脑实质中。在过去的80年里，研究揭示了“弥漫性侵袭”表型的两个关键特征，称为谢勒二级结构，包括神经元周围卫星组织（PS）和血管周围卫星组织（PVS）。然而，其机制仍然未知。我们建立了一个小鼠胶质瘤细胞系（IG27）通过操纵组蛋白H3K27M突变，经常窝藏在弥漫性内在脑桥胶质瘤，再现弥漫性侵袭表型，PS和PVS，颅内移植后，在小鼠脑。此外，为了将该小鼠模型的结果广泛应用于人类胶质瘤，我们分析了来自66名胶质瘤患者的数据。IG27细胞中H3K27乙酰化的增加激活了葡萄糖转运蛋白1（Glut1）的表达，并诱导有氧糖酵解和TCA循环激活，导致乳酸、乙酰辅酶A和癌代谢产物的产生，而与氧和葡萄糖水平无关。体内功能获得和丧失实验表明，Glut1控制胶质瘤细胞的PS，即与神经元的附着和接触。GLUT1也与胶质瘤患者的早期进展相关。在弥漫性胶质瘤小鼠模型中，靶向转运蛋白Glut1可抑制独特的表型“弥漫性侵袭”。这些工作为胶质瘤抗侵袭治疗提供了新的靶点，也为胶质瘤抗侵袭治疗提供了新的靶点。
Gliomas typically escape surgical resection and recur due to their “diffuse invasion” phenotype, enabling them to infiltrate diffusely into the normal brain parenchyma. Over the past 80 years, studies have revealed 2 key features of the “diffuse invasion” phenotype, designated the Scherer’s secondary structure, and include perineuronal satellitosis (PS) and perivascular satellitosis (PVS). However, the mechanisms are still unknown. We established a mouse glioma cell line (IG27) by manipulating the histone H3K27M mutation, frequently harboring in diffuse intrinsic pontine gliomas, that reproduced the diffuse invasion phenotype, PS and PVS, following intracranial transplantation in the mouse brain. Further, to broadly apply the results in this mouse model to human gliomas, we analyzed data from 66 glioma patients. Increased H3K27 acetylation in IG27 cells activated glucose transporter 1 (Glut1) expression and induced aerobic glycolysis and TCA cycle activation, leading to lactate, acetyl-CoA, and oncometabolite production irrespective of oxygen and glucose levels. Gain- and loss-of-function in vivo experiments demonstrated that Glut1 controls the PS of glioma cells, that is, attachment to and contact with neurons. GLUT1 is also associated with early progression in glioma patients. Targeting the transporter Glut1 suppresses the unique phenotype, “diffuse invasion” in the diffuse glioma mouse model. This work leads to promising therapeutic and potential useful imaging targets for anti-invasion in human gliomas widely.