Brain-wide neuronal circuit connectome of human glioblastoma

• 成果类型: Article
• 署名作者: 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; Goncalves, 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
• 署名单位: University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; Academia Sinica - Taiwan; Cornell University; Weill Cornell Medicine; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; Thomas Jefferson University; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; Johns Hopkins University; Chinese Academy of Sciences; Shenzhen Institute of Advanced Technology, CAS; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); University of Pennsylvania; University of Pennsylvania; University of Pennsylvania
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2201
• DOI: 10.1038/s41586-025-08634-7
• 发表日期: 2025-05-01
• 关键词: receptors; glioma; mechanisms; organoids; atlas; cells

摘要

Glioblastoma (GBM) infiltrates the brain and can be synaptically innervated by neurons, which drives tumour 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-mediated 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 in which rapid connectivity and transient activation of upstream neurons may lead to a long-lasting increase in tumour fitness.