Brain-wide neuronal circuit connectome of human glioblastoma

Yusha Sun, Xin Wang, Daniel Y. Zhang, Zhijian Zhang, Janardhan P. Bhattarai, Yingqi Wang, Kristen H. Park, Weifan Dong, Yun-Fen Hung, Qian Yang, Feng Zhang, Keerthi Rajamani, Shang Mu, Benjamin C. Kennedy, Yan Hong, Jamie Galanaugh, Abhijeet Sambangi, Sang Hoon Kim, Garrett Wheeler, Tiago Gonçalves, Qing Wang, Daniel H Geschwind, Riki Kawaguchi, Angela N. Viaene, Ingo Helbig, Sudha K. Kessler, Ahmet Hoke, Huadong Wang, Fuqiang Xu, Zev A. Binder, H. Isaac Chen, Emily Ling-Lin Pai, Sara Stone, MacLean P. Nasrallah, Kimberly M. Christian, Marc Fuccillo, Nicolas Toni, Zhuhao Wu, Hwai-Jong Cheng, Donald M. O’Rourke, Minghong Ma, Guo-li Ming () and Hongjun Song ()
Additional contact information
Yusha Sun: University of Pennsylvania
Xin Wang: University of Pennsylvania
Daniel Y. Zhang: University of Pennsylvania
Zhijian Zhang: University of Pennsylvania
Janardhan P. Bhattarai: University of Pennsylvania
Yingqi Wang: University of Pennsylvania
Kristen H. Park: University of Pennsylvania
Weifan Dong: University of Pennsylvania
Yun-Fen Hung: Academia Sinica
Qian Yang: University of Pennsylvania
Feng Zhang: University of Pennsylvania
Keerthi Rajamani: Weill Cornell Medicine
Shang Mu: Weill Cornell Medicine
Benjamin C. Kennedy: University of Pennsylvania
Yan Hong: University of Pennsylvania
Jamie Galanaugh: University of Pennsylvania
Abhijeet Sambangi: Thomas Jefferson University Hospital
Sang Hoon Kim: University of Pennsylvania
Garrett Wheeler: Albert Einstein College of Medicine
Tiago Gonçalves: Albert Einstein College of Medicine
Qing Wang: University of California Los Angeles
Daniel H Geschwind: University of California Los Angeles
Riki Kawaguchi: University of California Los Angeles
Angela N. Viaene: Children’s Hospital of Philadelphia
Ingo Helbig: Children’s Hospital of Philadelphia
Sudha K. Kessler: Children’s Hospital of Philadelphia
Ahmet Hoke: Johns Hopkins University School of Medicine
Huadong Wang: Chinese Academy of Sciences
Fuqiang Xu: Chinese Academy of Sciences
Zev A. Binder: University of Pennsylvania
H. Isaac Chen: University of Pennsylvania
Emily Ling-Lin Pai: University of Pennsylvania
Sara Stone: University of Pennsylvania
MacLean P. Nasrallah: University of Pennsylvania
Kimberly M. Christian: University of Pennsylvania
Marc Fuccillo: University of Pennsylvania
Nicolas Toni: Lausanne University Hospital
Zhuhao Wu: Weill Cornell Medicine
Hwai-Jong Cheng: Academia Sinica
Donald M. O’Rourke: University of Pennsylvania
Minghong Ma: University of Pennsylvania
Guo-li Ming: University of Pennsylvania
Hongjun Song: University of Pennsylvania

Nature, 2025, vol. 641, issue 8061, 222-231

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41586-025-08634-7

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