脑瘤,卞修武院士,胶质母细胞瘤 z-bio 2025-08-26 3460

　　Glioblastoma (GBM) is the most common and aggressive primary brain tumor with a very poor prognosis in patients and a median survival period usually does not exceed 15 months. In recent years, more and more studies have shown that GBM does not exist in isolation, but can interact closely with peripheral neural circuits, and even integrate into neural networks to promote its own proliferation and invasion through neural activity.

　　Previous studies have focused on the role of glutamategic signals in tumor progression, but little is still known about how other neurotransmitter systems (such as the cholinergic system) participate in regulating GBM, especially long-range neural input.

　　On August 18, 2025, Chen Tunan, Bian Xiuwu, Feng Hua, Li Fei, Anhui Medical University Wang Yuhai and others published a research paper entitled "Long-range Cholinergic Input Promotes Glioblastoma Progression" at Cancer Cell (IF=44.5).

　　The research team used single-synaptic rabies virus tracing technology to systematically draw the neural input map of human GBM transplanted tumors across the brain, revealing its connection pattern with local and long-distance neurons.

　　This article revolves around "How neuron-glioma interactions affect the progress of glioblastoma (GBM)". The research ideas follow the logical progression of "discovering connection patterns → verifying functional effects → analytical mechanisms → exploring clinical transformation".

　　GBM is known to be integrated into neural circuits, and local glutamategic synaptic input has been shown to promote tumor progression, but the overall architecture of neuron-glioma connections (especially the role of remote neural circuits and diverse neurotransmitter systems) is not yet clear. Based on this, the research focuses on: What is the connection pattern between GBM and whole-brain neurons? Does remote neural input (especially the neuromodulation system) participate and affect GBM progress?

　　Draw the whole-brain neuron-glioma connection map

　　In order to analyze the connection architecture of neuron-glioma, the study used single-synaptic rabies virus tracing technology to conduct whole-brain input mapping of patient-derived GBM cells transplanted into different brain regions such as the prefrontal cortex, hippocampus, caudal puta, etc., combined with fMOST whole-brain imaging and molecular marker analysis, it was found that:

　　The connection pattern has spatial organizational rules: local input is mainly glutamate neurons, remote input comes from subcortical nuclei, and there are various types of neurotransmitters;

　　Basal forebrain cholinergic projections (such as Broca beveled nucleus) are conservative remote inputs across tumor locations and patient sources, and are the core research subjects.

　　Verify the connection between the remote cholinergic input and GBM

　　After clarifying the structural connection, it was observed through immunoelectromics that there was a symmetric synaptic structure between the basal forebrain cholinergic axons and GBM cells, which was consistent with the typical morphology of cholinergic synaptics.

　　Further, optogenetic activation of cholinergic neurons can trigger sustained calcium transients in GBM cells, and this reaction can be completely blocked by acetylcholine receptor antagonist, confirming acetylcholine (ACh)-mediated functional ligation.

　　Analyzing the mechanism by which cholinergic input promotes GBM progress

　　Regarding "How cholinergic input drives GBM progress", the study explores three aspects: receptor, loop specificity, and coordination with other signals:

　　Key receptor identification: Through CRISPR knockout experiment, it was found that knocking out the muscarinic receptor CHRM3 alone can inhibit ACh-induced GBM proliferation, and the high expression of CHRM3 is related to poor patient prognosis, confirming the necessity of CHRM3;

　　Circuit specificity: When GBM is transplanted to the medulla of the medulla without basal forebrain cholinergic input, activation of cholinergic neurons cannot promote tumor growth, confirming that the effect depends on direct neural connections;

　　Synergistic with glutamategic signal: Calcium imaging shows that ACh and glutamate can superimpose the calcium transients in GBM cells. Transcriptome analysis found that there was a time difference in the regulation of gene expression (glutamate effect is short and ACh is durable), suggesting a non-redundant synergistic mechanism.

　　Explore clinical transformation potential and verify treatment strategies

　　Based on mechanism research, the anti-tumor effects of approved drugs are tested, providing a basis for clinical applications:

　　The muscarinic receptor antagonist hyosamine can inhibit GBM growth and prolong the survival of model mice;

　　The acetylcholinesterase inhibitor donepezil (increasing ACh levels) will accelerate the progression of GBM, suggesting that clinical use should be used with caution;

　　Combined blocking of the cholinergic (hyopamine) and glutamate (perampanel) pathways, or combined with the standard chemotherapeutic drug temozolomide, produces superimposed anti-tumor effects and verify the potential of combined treatment.

　　In summary, from "structural connection" to "functional mechanism" to "clinical transformation", the systematic reveals the role of remote cholinergic input in the progression of GBM, providing new ideas for the treatment of targeted nerve-tumor interactions.