Long-range cholinergic input promotes glioblastoma progression

  • Cancer Cell. 2025 Aug 12:S1535-6108(25)00330-7. doi: 10.1016/j.ccell.2025.07.024.
Yang Yang  1 ,  Chuanyan Yang  2 ,  Xuezhu Chen  3 ,  Yibin Jiang  2 ,  Xuejiao Lei  2 ,  Kang Ma  2 ,  Yulian Quan  2 ,  Tianran Li  4 ,  Chenfu Guo  2 ,  Yijing Meng  5 ,  Lin Kang  5 ,  Xinyu Zhang  5 ,  Long Jin  6 ,  Jiafeng Huang  4 ,  Ning Mu  2 ,  Zexuan Yan  4 ,  Qinghua Ma  4 ,  Shuai Wang  4 ,  Yanxia Wang  4 ,  Yong-Ning Shang  7 ,  Cong Chen  4 ,  Yu Shi  8 ,  Shukun Hu  9 ,  Likun Yang  5 ,  Chuan Lan  2 ,  Rong Hu  2 ,  Ying Zhang  3 ,  Xia Li  10 ,  Yunqing Li  10 ,  Chong Liu  11 ,  Yu-Hai Wang  12 ,  Fei Li  13 ,  Hua Feng  14 ,  Xiu-Wu Bian  15 ,  Tunan Chen  16
Affiliations
  • 1. Institute of Pathology & Southwest Cancer Center, Glioma Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), and The Key Laboratory of Tumor Immunopathology, The Ministry of Education of China, Chongqing 400038, China; Department of Neurosurgery, Glioma Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Department of Neurosurgery, No.904 Hospital, Anhui Medical University, Wuxi 214044, China.
  • 2. Department of Neurosurgery, Glioma Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
  • 3. Department of Pathology, Public Health Medical Center, Chongqing 400036, China.
  • 4. Institute of Pathology & Southwest Cancer Center, Glioma Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), and The Key Laboratory of Tumor Immunopathology, The Ministry of Education of China, Chongqing 400038, China.
  • 5. Department of Neurosurgery, No.904 Hospital, Anhui Medical University, Wuxi 214044, China.
  • 6. Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
  • 7. Department of Ultrasound, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
  • 8. Institute of Pathology & Southwest Cancer Center, Glioma Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), and The Key Laboratory of Tumor Immunopathology, The Ministry of Education of China, Chongqing 400038, China; Chongqing Institute of Advanced Pathology, Jinfeng Laboratory, Chongqing 400039, China.
  • 9. Department of Neurosurgery, Affiliated Huashan Hospital, Fudan University, Shanghai 200040, China.
  • 10. Department of Anatomy and K.K. Leung Brain Research Centre, Fourth Military Medical University, Xi'an 710032, China.
  • 11. Department of Neurosurgery of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Chongqing Institute of Advanced Pathology, Jinfeng Laboratory, Chongqing 400039, China.
  • 12. Department of Neurosurgery, No.904 Hospital, Anhui Medical University, Wuxi 214044, China. Electronic address: [email protected].
  • 13. Department of Neurosurgery, Glioma Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China. Electronic address: [email protected].
  • 14. Department of Neurosurgery, Glioma Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China. Electronic address: [email protected].
  • 15. Institute of Pathology & Southwest Cancer Center, Glioma Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), and The Key Laboratory of Tumor Immunopathology, The Ministry of Education of China, Chongqing 400038, China; Chongqing Institute of Advanced Pathology, Jinfeng Laboratory, Chongqing 400039, China. Electronic address: [email protected].
  • 16. Department of Neurosurgery, Glioma Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China. Electronic address: [email protected].
PMID: 40829591 DOI: 10.1016/j.ccell.2025.07.024
Abstract

Glioblastoma (GBM), the most aggressive primary brain tumor, is shaped by its integration into neural networks. While glutamatergic input is linked to tumor progression, the broader architecture and function of neuron-glioma connectomes remain unclear. Using monosynaptic rabies tracing, we map brain-wide neural input to patient-derived xenografts and reveal a consistent organizational logic: local inputs are primarily glutamatergic, while long-range connections exhibit diverse neurotransmitter profiles, with basal forebrain cholinergic projections emerging as a conserved input across sites. Functionally, presynaptic acetylcholine release promotes GBM progression through muscarinic receptor CHRM3 in a circuit-specific manner. Mechanistically, glutamatergic and cholinergic signals converge to enhance glioma calcium transients but diverge in temporal transcriptional control, with their dual blockade producing additive anti-tumor effects. Therapeutically, the anticholinergic drug scopolamine attenuates glioma growth, whereas the acetylcholinesterase inhibitor donepezil exacerbates disease. These findings reveal the complexity of neuron-glioma connectivity, highlighting long-range neuromodulatory pathways as promising therapeutic targets in GBM.

Keywords
CHRM3; cholinergic input; diagonal band of Broca; donepezil; glioblastoma; glutamatergic input; neural circuit manipulation; neuro-glioma interaction; rabies virus; scopolamine.
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