美国宾夕法尼亚大学Hongjun Song和Guo-li Ming共同合作，近期取得重要工作进展。他们研究绘制了人脑胶质母细胞瘤的全脑神经元回路连接图谱。相关研究成果2025年1月16日在线发表于《自然》杂志上。

据介绍，胶质母细胞瘤（GBM）会浸润大脑，且能被神经元以突触方式支配，这会推动肿瘤进展。目前已确定的作用于GBM细胞的突触输入大多是短程的且为谷氨酸能。GBM融入全脑神经元回路的程度仍不明确。

研究人员运用狂犬病病毒和单纯疱疹病毒介导的跨单突触示踪技术，系统研究了移植到成年小鼠体内的人GBM类器官的回路整合情况。研究人员发现，来自多位患者的GBM细胞能迅速融入大脑中多样的局部和长程神经回路。除了谷氨酸能输入，研究人员还识别出各种神经调节输入，包括基底前脑胆碱能神经元与GBM细胞之间的突触。

急性乙酰胆碱刺激通过代谢型毒蕈碱乙酰胆碱受体3（CHRM3），诱导GBM细胞内钙振荡的持久升高，并将GBM细胞转录重编程为更具运动性的状态。CHRM3的激活会促进GBM 细胞的运动性，而其下调则会抑制GBM细胞的运动性，并延长小鼠存活时间。

总之，这一研究揭示了人GBM细胞具有惊人的能力，能够快速且稳固地融入不同神经递质系统的多种解剖学神经元网络。这一研究结果进一步支持了这样一种模型，即上游神经元的快速连接和瞬时激活可能导致肿瘤适应性的持久增强。

附：英文原文

Title: Brain-wide neuronal circuit connectome of human glioblastoma

Author: Sun, Yusha, Wang, Xin, Zhang, Daniel Y., Zhang, Zhijian, Bhattarai, Janardhan P., Wang, Yingqi, Park, Kristen H., Dong, Weifan, Hung, Yun-Fen, Yang, Qian, Zhang, Feng, Rajamani, Keerthi, Mu, Shang, Kennedy, Benjamin C., Hong, Yan, Galanaugh, Jamie, Sambangi, Abhijeet, Kim, Sang Hoon, Wheeler, Garrett, Gonalves, Tiago, Wang, Qing, Geschwind, Daniel, Kawaguchi, Riki, Viaene, Angela N., Helbig, Ingo, Kessler, Sudha K., Hoke, Ahmet, Wang, Huadong, Xu, Fuqiang, Binder, Zev A., Chen, H. Isaac, Pai, Emily Ling-Lin, Stone, Sara, Nasrallah, MacLean P., Christian, Kimberly M., Fuccillo, Marc, Toni, Nicolas, Wu, Zhuhao, Cheng, Hwai-Jong, ORourke, Donald M., Ma, Minghong, Ming, Guo-li, Song, Hongjun

Issue&Volume: 2025-01-16

Abstract: Glioblastoma (GBM) infiltrates the brain and can be synaptically innervated by neurons, which drives tumor progression1,2. Synaptic inputs onto GBM cells identified so far are largely short-range and glutamatergic3,4. The extent of GBM integration into the brain-wide neuronal circuitry remains unclear. Here we applied rabies virus- and herpes simplex virus-mediated trans-monosynaptic tracing5,6 to systematically investigate circuit integration of human GBM organoids transplanted into adult mice. We found that GBM cells from multiple patients rapidly integrate into diverse local and long-range neural circuits across the brain. Beyond glutamatergic inputs, we identified various neuromodulatory inputs, including synapses between basal forebrain cholinergic neurons and GBM cells. Acute acetylcholine stimulation induces long-lasting elevation of calcium oscillations and transcriptional reprogramming of GBM cells into a more motile state via the metabotropic CHRM3 receptor. CHRM3 activation promotes GBM cell motility, whereas its downregulation suppresses GBM cell motility and prolongs mouse survival. Together, these results reveal the striking capacity for human GBM cells to rapidly and robustly integrate into anatomically diverse neuronal networks of different neurotransmitter systems. Our findings further support a model wherein rapid connectivity and transient activation of upstream neurons may lead to a long-lasting increase in tumor fitness.

DOI: 10.1038/s41586-025-08634-7

Source: https://www.nature.com/articles/s41586-025-08634-7