A PROGNOSTIC HUMAN BRAIN NETWORK FOR DIFFUSE MIDLINE GLIOMA

Abstract AIMS Diffuse midline glioma (DMG) are near-universally lethal tumours of the paediatric central nervous system. In animal models, DMG form brain-wide, integrated networks through neuron-to-glioma synapses and glioma- to-glioma gap junctional coupling. This extensive connectivity robustly promotes DMG growth and inva- sion through paracrine mechanisms and direct, neuron-to-glioma synapses. The organisation and clinical im- plications of these connections in the living human brain, however, remain to be elucidated. METHODS We leverage multimodal, real-world clinical data from 125 children with primary DMG (discovery dataset) and paediatric connectomic data (n=1000 children) to compute the brain-wide connectivity profile of DMG using lesion network mapping. RESULTS Pontine and thalamic DMG map to a unified brain network associated with patient short-term survival and defined by connectivity with the brainstem, cerebellum, limbic system, motor cortex, and insular cortex (DMG network; PFWE<0.01). Tumour connectivity with the DMG network was independently predictive of patient over- all survival in an external, multicentre validation cohort of 125 children with DMG (AUROC=0.95). Moreover, incidental surgical resection of thalamic DMG tissue with high connectivity to the DMG network conferred a significant survival advantage (P=0.02; median overall survival 9.2 vs. 30.5 months). Tumour growth pat- terns demonstrated directional tropism to DMG network connectivity peaks (Spearman’s ρ=0.54; PFWE=0.03). Orthogonal DMG network characterisation using multi-tracer positron emission tomography identified peak, in-network neurometabolic changes spatiotemporally aligned with the peak age incidence of DMG (R2=0.41) as well as dominant chemoarchitectural patterns of serotonergic, cholinergic, and noradrenergic signalling (R2adj=0.62). Finally, DMG with higher network-to-tumour connectivity exhibited epigenetic enrichment of pro- grammes promoting neurogenesis, neural stemness, and synaptic integration. CONCLUSION Collectively, these data provide real-world evidence for neural activity modulating DMG growth in humans, as previously described only in animal models, and are consistent with the hypothesis that DMG exploit otherwise healthy brain circuits to establish an environment that promotes tumour growth across multiple connectomic, neuromodulatory, and neurometabolic scales.

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Journal
Neuro-Oncology
Published
2025-09-01
DOI
https://doi.org/10.1093/neuonc/noaf185.044
Primary Topic
Glioma Diagnosis and Treatment
Type
article
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article

A PROGNOSTIC HUMAN BRAIN NETWORK FOR DIFFUSE MIDLINE GLIOMA

Maura E. Ryan, Pierre‐Étienne Jacques, Sniya Sudhakar, Humsa S. Venkatesh et al.
Neuro-Oncology
Glioma Diagnosis and Treatment
article

A PROGNOSTIC HUMAN BRAIN NETWORK FOR DIFFUSE MIDLINE GLIOMA

Maura E. Ryan, Pierre‐Étienne Jacques, Sniya Sudhakar, Humsa S. Venkatesh, Darren Hargrave, Peter T. Fox, Michelle Monje, Chris Jones, Andrés Morales, Parthiv Haldipur, Margaret L. Lind, Enrico De Vita, Kathleen Dorris, T. J. Stone, Adam L. Green, Harith Akram, Eleonora Piccirilli, Marie T. Krüger, Jernej Avsenik, Deborah Ridout, Alexander L. Cohen, Asthik Biswas, Kshitij Mankad, Frédéric Schaper, Alan Mackay, Kristian Aquilina, Rajan Patel, Andrew M. Donson, Jordi Muchart, Paul S. Morgan, Jai Sidpra, Ludvic Zrinzo, Mingrui Zhao, Suely Fazio Ferraciolli, Bruno S Peres, Francisco Sepulveda, Raffaella Scotto Opipari, Andreas Horn, Miss Cristina Alemán-Charlet, Prof Leandro T Lucato, Prof David M Mirsky
article en

Abstract

Abstract AIMS Diffuse midline glioma (DMG) are near-universally lethal tumours of the paediatric central nervous system. In animal models, DMG form brain-wide, integrated networks through neuron-to-glioma synapses and glioma- to-glioma gap junctional coupling. This extensive connectivity robustly promotes DMG growth and inva- sion through paracrine mechanisms and direct, neuron-to-glioma synapses. The organisation and clinical im- plications of these connections in the living human brain, however, remain to be elucidated. METHODS We leverage multimodal, real-world clinical data from 125 children with primary DMG (discovery dataset) and paediatric connectomic data (n=1000 children) to compute the brain-wide connectivity profile of DMG using lesion network mapping. RESULTS Pontine and thalamic DMG map to a unified brain network associated with patient short-term survival and defined by connectivity with the brainstem, cerebellum, limbic system, motor cortex, and insular cortex (DMG network; PFWE<0.01). Tumour connectivity with the DMG network was independently predictive of patient over- all survival in an external, multicentre validation cohort of 125 children with DMG (AUROC=0.95). Moreover, incidental surgical resection of thalamic DMG tissue with high connectivity to the DMG network conferred a significant survival advantage (P=0.02; median overall survival 9.2 vs. 30.5 months). Tumour growth pat- terns demonstrated directional tropism to DMG network connectivity peaks (Spearman’s ρ=0.54; PFWE=0.03). Orthogonal DMG network characterisation using multi-tracer positron emission tomography identified peak, in-network neurometabolic changes spatiotemporally aligned with the peak age incidence of DMG (R2=0.41) as well as dominant chemoarchitectural patterns of serotonergic, cholinergic, and noradrenergic signalling (R2adj=0.62). Finally, DMG with higher network-to-tumour connectivity exhibited epigenetic enrichment of pro- grammes promoting neurogenesis, neural stemness, and synaptic integration. CONCLUSION Collectively, these data provide real-world evidence for neural activity modulating DMG growth in humans, as previously described only in animal models, and are consistent with the hypothesis that DMG exploit otherwise healthy brain circuits to establish an environment that promotes tumour growth across multiple connectomic, neuromodulatory, and neurometabolic scales.

Neuro-OncologyVol. 27(Supplement_2)
Northwestern University (US), Boston Children's Hospital (US), Lurie Children's Hospital (US), Center for Infectious Disease Research (US), Hospital Sant Joan de Déu Barcelona (ES), Nottingham University Hospitals NHS Trust (GB), Institute of Cancer Research (GB), Great Ormond Street Hospital (GB), Great Ormond Street Hospital for Children NHS Foundation Trust (GB), Ljubljana University Medical Centre (SI), Children's Hospital Colorado (US), Circuit Therapeutics (United States) (US), Bambino Gesù Children's Hospital (IT), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR), Texas Children's Hospital (US), National Hospital for Neurology and Neurosurgery (GB), University College London (GB), University of Colorado Denver (US), Stanford University (US)
Openalex Percentile: Top 68%
Glioma Diagnosis and Treatment
DOIOpen Access PDFOpenAlex
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