Glioblastoma-Secreted C1QL1 Orchestrates Tumor Microtube Expansion and Neural Synaptic Pruning to Drive Malignant Synapse Formation and Recurrence

  • Cancer Discov. 2026 Jun 1;16(6):1176-1199. doi: 10.1158/2159-8290.CD-25-1123.
Chaoqiong Ding  #  1  2 ,  Jiayi Dong  #  1  3 ,  Zhenzhong Pan  #  1 ,  Shijie Liu  #  1 ,  Qiuyue Song  1 ,  Gaoxia Yang  1  2 ,  Yuling Peng  1  3 ,  Chuanxing Xie  1 ,  Zongyao Huang  1 ,  Wei Yao  4  5 ,  Mengnan Wu  4  5 ,  Yi Zhong  4  5 ,  Wei Zhang  6 ,  Yan Zhang  3 ,  Songhua Wang  7  8 ,  Weiwei Ma  4  5 ,  Yuan Wang  1  2
Affiliations
  • 1. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
  • 2. Tianfu Jincheng Laboratory, Chengdu, China.
  • 3. National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
  • 4. School of Life Sciences, Tsinghua University, Beijing, China.
  • 5. Beijing Joekai Biotechnology LLC, Beijing, China.
  • 6. Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
  • 7. Jiangxi Provincial Key Laboratory of Organic Functional Molecules, Institute of Organic Chemistry, Jiangxi Science and Technology Normal University, Nanchang, China.
  • 8. School of Sports and Health, Jiangxi Science and Technology Normal University, Nanchang, China.
  • # Contributed equally.
PMID: 41747254 DOI: 10.1158/2159-8290.CD-25-1123
Abstract

Glioblastoma (GBM) cells form neuron-to-glioma malignant synapses on neurite-like tumor microtubes (TM), driving infiltrative growth and recurrence. The mechanisms underlying coordinated cross-talk among GBM cells and with neurons to favor malignant over normal synapses remain largely unknown. Here, we demonstrate that glioma-secreted C1QL1 is a key messenger for glioma-neuron and glioma-glioma cross-talk to drive TM expansion and malignant synapse formation. C1QL1 binds to its receptor BAI3 on neighboring neurons and GBM cells, activating RAC1-mediated Cytoskeleton rearrangement to prune normal synapses and outgrow TMs, promoting malignant synapse and glioma network formation. Targeted treatment with a non-GEF-targeting, first-in-class RAC1 inhibitor rescues C1QL1-mediated synaptic pruning, inhibiting TMs and malignant synapses to impede glioma recurrence. Our findings elucidate how cross-talk among GBM cells and neurons allows infiltrating GBM cells to sculpt and integrate into the existing neural network, highlighting a therapeutic strategy against GBM recurrence through simultaneous inhibition of TMs and glioma-induced synaptic pruning.

Significance: Our study identifies C1QL1 as a key messenger secreted by infiltrating glioma cells, orchestrating glioma-glioma and glioma-neuron cross-talk to induce TM expansion and neural synaptic pruning, driving malignant synapse formation and recurrence through a C1QL1-BAI3-RAC1 axis. Targeting RAC1 with a non-GEF-targeting RAC1 inhibitor could impede glioma recurrence and improve survival. See related commentary by Li and Borniger, p. 1047.

Products