德国海德堡大学Frank Winkler研究团队发现，胶质瘤网络中的自主节律性活动驱动脑瘤生长。该研究于2022年12月14日在线发表于国际一流学术期刊《自然》。

研究人员描述了胶质母细胞瘤细胞网络如何囊括一小批高度活跃的胶质母细胞，这些细胞显示出有节奏的Ca²⁺振荡，并与其他细胞相连。它们自主的周期性Ca²⁺瞬变先于其他网络连接的细胞的Ca²⁺瞬变，激活了依赖频率的MAPK和NF-κB途径。数学网络分析显示，胶质母细胞瘤网络拓扑结构遵循一定的特性，周期性肿瘤细胞经常位于网络中心。

这种网络设计能够抵抗随机损害，但容易失去其关键枢纽。通过选择性地对周期性肿瘤细胞进行物理去除，或通过对钾通道KCa3.1（也称为IK1、SK4或KCNN4）的遗传或药物干扰来锁定自主节律性活动，强烈损害了全局网络通信。这导致整个网络内的肿瘤细胞活力明显下降，小鼠的肿瘤生长减少，动物生存期延长。胶质母细胞瘤网络对周期性Ca²⁺活动的依赖性产生了一种脆弱性，可用于开发新型疗法，如使用KCa3.1抑制药物。

据了解，弥漫性胶质瘤，特别是胶质母细胞瘤，是无法治愈的脑肿瘤。它们的特点是由相互连接的脑瘤细胞组成的网络，通过Ca²⁺瞬变进行交流。然而，网络的结构和通信策略以及这些如何影响肿瘤生物学仍然是未知的。

附：英文原文

Title: Autonomous rhythmic activity in glioma networks drives brain tumour growth

Author: Hausmann, David, Hoffmann, Dirk C., Venkataramani, Varun, Jung, Erik, Horschitz, Sandra, Tetzlaff, Svenja K., Jabali, Ammar, Hai, Ling, Kessler, Tobias, Azoin, Daniel D., Weil, Sophie, Kourtesakis, Alexandros, Sievers, Philipp, Habel, Antje, Breckwoldt, Michael O., Karreman, Matthia A., Ratliff, Miriam, Messmer, Julia M., Yang, Yvonne, Reyhan, Ekin, Wendler, Susann, Lb, Cathrin, Mayer, Chant, Figarella, Katherine, Osswald, Matthias, Solecki, Gergely, Sahm, Felix, Garaschuk, Olga, Kuner, Thomas, Koch, Philipp, Schlesner, Matthias, Wick, Wolfgang, Winkler, Frank

Issue&Volume: 2022-12-14

Abstract: Diffuse gliomas, particularly glioblastomas, are incurable brain tumours1. They are characterized by networks of interconnected brain tumour cells that communicate via Ca2+ transients2,3,4,5,6. However, the networks’ architecture and communication strategy and how these influence tumour biology remain unknown. Here we describe how glioblastoma cell networks include a small, plastic population of highly active glioblastoma cells that display rhythmic Ca2+ oscillations and are particularly connected to others. Their autonomous periodic Ca2+ transients preceded Ca2+ transients of other network-connected cells, activating the frequency-dependent MAPK and NF-κB pathways. Mathematical network analysis revealed that glioblastoma network topology follows scale-free and small-world properties, with periodic tumour cells frequently located in network hubs. This network design enabled resistance against random damage but was vulnerable to losing its key hubs. Targeting of autonomous rhythmic activity by selective physical ablation of periodic tumour cells or by genetic or pharmacological interference with the potassium channel KCa3.1 (also known as IK1, SK4 or KCNN4) strongly compromised global network communication. This led to a marked reduction of tumour cell viability within the entire network, reduced tumour growth in mice and extended animal survival. The dependency of glioblastoma networks on periodic Ca2+ activity generates a vulnerability7 that can be exploited for the development of novel therapies, such as with KCa3.1-inhibiting drugs.

DOI: 10.1038/s41586-022-05520-4

Source: https://www.nature.com/articles/s41586-022-05520-4