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

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.