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, Gonçalves Tiago, Wang Qing, Geschwind Daniel H, Kawaguchi Riki, Viaene Angela N, Helbig Ingo, Kessler Sudha K, Hoke Ahmet, Wang Huadong, Xu Fuqiang, Binder Zev A, Isaac Chen H, Pai Emily Ling-Lin, Stone Sara, Nasrallah MacLean P, Christian Kimberly M, Fuccillo Marc, Toni Nicolas, Wu Zhuhao, Cheng Hwai-Jong, O'Rourke Donald M, Ma Minghong, Ming Guo-Li, Song Hongjun
Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Nature. 2025 May;641(8061):222-231. doi: 10.1038/s41586-025-08634-7. Epub 2025 Jan 16.
Glioblastoma (GBM) infiltrates the brain and can be synaptically innervated by neurons, which drives tumour progression. Synaptic inputs onto GBM cells identified so far are largely short range and glutamatergic. The extent of GBM integration into the brain-wide neuronal circuitry remains unclear. Here we applied rabies virus-mediated and herpes simplex virus-mediated trans-monosynaptic tracing 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 in which rapid connectivity and transient activation of upstream neurons may lead to a long-lasting increase in tumour fitness.
胶质母细胞瘤（GBM）会浸润大脑，且可被神经元进行突触支配，这会驱动肿瘤进展。迄今为止，在GBM细胞上识别出的突触输入大多是短程的且为谷氨酸能的。GBM融入全脑神经元回路的程度仍不清楚。在此，我们应用狂犬病病毒介导和单纯疱疹病毒介导的跨单突触追踪技术，系统地研究移植到成年小鼠体内的人GBM类器官的回路整合情况。我们发现，来自多名患者的GBM细胞能迅速融入大脑中不同的局部和长程神经回路。除了谷氨酸能输入外，我们还识别出了各种神经调节输入，包括基底前脑胆碱能神经元与GBM细胞之间的突触。急性乙酰胆碱刺激会通过代谢型CHRM3受体诱导GBM细胞的钙振荡持久升高，并使其转录重编程为更具迁移性的状态。CHRM3激活会促进GBM细胞迁移，而其下调则会抑制GBM细胞迁移并延长小鼠存活时间。总之，这些结果揭示了人GBM细胞迅速且有力地融入不同神经递质系统的解剖学上多样的神经元网络的显著能力。我们的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短暂激活可能会导致肿瘤适应性的长期增加。
