Brain-wide neuronal circuit connectome of human glioblastoma by Yusha Sun1,25, Xin Wang2,25, Daniel Y. Zhang3, Zhijian Zhang2, Janardhan P. Bhattarai2, ISBN 101038/S41586025086347 instant download

Brain-wide neuronal circuit connectome of human glioblastoma by Yusha Sun1,25, Xin Wang2,25, Daniel Y. Zhang3, Zhijian Zhang2, Janardhan P. Bhattarai2, ISBN 101038/S41586025086347 instant download

Glioblastoma (GBM) infltrates the brain and can be synaptically innervated by neurons, which drives tumour progression1,2. Synaptic inputs onto GBM cells identifed 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 identifed 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 diferent neurotransmitter systems. Our fndings further support a model in which rapid connectivity and transient activation of upstream neurons may lead to a long-lasting increase in tumour ftness.