Glutamatergic synaptic input to glioma cells drives brain tumour progression
Glutamatergic synaptic input to glioma cells drives brain tumour progression
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DOI：
10.1038/s41586-019-1564-x
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发表时间：
2019-09-26
期刊：
影响因子：
64.8
通讯作者：
Kuner, Thomas
中科院分区：
文献类型：
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作者：
Venkataramani, Varun;Tanev, Dimitar Ivanov;Kuner, Thomas
由肿瘤微管连接的通信肿瘤细胞网络介导了不可治愈的神经胶质瘤的进展。此外，神经元活动可以通过非突触旁分泌和自分泌机制促进胶质瘤细胞的恶性行为。在这里，我们报告了神经元和神经胶质瘤细胞在不同的疾病模型和人类肿瘤之间的直接沟通渠道：功能真正的化学突触突触前神经元和突触后神经胶质瘤细胞之间。这些神经胶质细胞突触显示出典型的突触超微结构，位于肿瘤微管上，并产生由AMPA亚型的谷氨酸受体介导的突触后电流。神经元活动，包括癫痫条件产生同步钙瞬变在肿瘤微管连接神经胶质瘤网络。AMPA受体的胶质瘤细胞特异性遗传干扰降低了肿瘤微管阳性肿瘤细胞的钙相关侵袭性和胶质瘤生长麻醉和AMPA受体拮抗剂perampanel也分别降低了侵袭和生长。这些发现揭示了神经元和胶质瘤细胞之间具有潜在临床意义的生物学相关的直接突触通信。
A network of communicating tumour cells that is connected by tumour microtubes mediates the progression of incurable gliomas. Moreover, neuronal activity can foster malignant behaviour of glioma cells by non-synaptic paracrine and autocrine mechanisms. Here we report a direct communication channel between neurons and glioma cells in different disease models and human tumours: functional bona fide chemical synapses between presynaptic neurons and postsynaptic glioma cells. These neurogliomal synapses show a typical synaptic ultrastructure, are located on tumour microtubes, and produce postsynaptic currents that are mediated by glutamate receptors of the AMPA subtype. Neuronal activity including epileptic conditions generates synchronised calcium transients in tumour-microtube-connected glioma networks. Glioma-cell-specific genetic perturbation of AMPA receptors reduces calcium-related invasiveness of tumour-microtube-positive tumour cells and glioma growth. Invasion and growth are also reduced by anaesthesia and the AMPA receptor antagonist perampanel, respectively. These findings reveal a biologically relevant direct synaptic communication between neurons and glioma cells with potential clinical implications.