A prognostic human brain network for diffuse midline glioma

Main

Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) are the leading cause of solid-tumour-related death in children which despite clinical trials over the past two decades, retain notorious therapeutic resistance and near-universal lethality 2 , 13 . A major clinical challenge limiting the efficacy of conventional therapeutic approaches, and recognized in original definitions of the disease, is the extensive infiltration of healthy brain parenchyma 14 . This distributed, brain-wide pattern of tumour progression, including to distant brain regions such as the frontal and temporal poles, is insufficiently explained by current models of tumour evolution 15 , 16 , 17 . Recent work has established DMG integration and communication with otherwise healthy neural circuits through both paracrine signalling (brain-derived neurotrophic factor (BDNF) and neuroligin-3 (NLGN3)) 4 , 7 , 8 and bona fide, electrophysiologically functional neuron-to-glioma synapses across a diverse neurotransmitter repertoire, including glutamatergic, calcium-permeable AMPA receptor-mediated 3 , 4 ; cholinergic M1–M3 receptor-mediated 5 ; and GABAergic GABA A  receptor-mediated 6 neuron-to-glioma synapses. In animal models, depolarization of glioma cell membranes drives tumour growth through voltage-dependent mechanisms that remain to be fully elucidated 3 , 4 . Neuronal cell somata local to or distant from and projecting onto malignant cells engage brain-wide neural populations in glioma circuits, activity from which acts as a putative driver of tumour progression 5 , 9 , 18 . For example, long-range cholinergic projections from the midbrain pedunculopontine and laterodorsal tegmental nuclei, respectively, promote the circuit-specific growth of pontine and thalamic DMG in preclinical models 5 . Although the impact of other neuromodulatory neurons remains to be fully explored, early preclinical reports suggest that serotonergic projections from the dorsal and median raphe promote the circuit-specific growth of pontine, thalamic and cortical DMG, while noradrenergic projections from the locus coeruleus also promote DMG growth 9 , 18 .

Thus far, attempts to map the brain-wide neural circuits implicated in tumour growth have been restricted to mouse models, which offer an incomplete representation of human-specific neurobiology and therapeutic relevance. Further, the distinct spatiotemporal pattern of DMG incidence, such that pontine and thalamic tumours peak in incidence during early childhood and early adolescence, respectively, suggests tumour exploitation of an underlying neurodevelopmental process. Here, using patient clinical data and human paediatric connectomic data, we define the spatial topography of brain network connections associated with short-term survival in children with DMG and delineate circuit-specific trajectories of DMG tumour growth.

Tumour network mapping

We first studied a discovery cohort of 125 children aged less than 18 years with primary pontine DMG/DIPG ( n  = 106), or thalamic DMG ( n  = 19), treated at Great Ormond Street Hospital for Children (GOSH; Fig. 1a and Supplementary Table 1 ). As pontine biopsies were historically not performed 19 , children meeting clinical diagnostic criteria for DIPG 20 , 21 , 22 and with a disease course consistent with short-term (<18-month) 23 overall survival were included. In line with the World Health Organisation 2021 definition of the disease 1 , biopsied tumours are classified as DMG, H3K27-altered, while non-biopsied pontine tumours are classified as DIPG. Throughout, reproducibility of findings is demonstrated for the combined (DMG/DIPG) patient cohort and across restricted cohorts of children with biopsied pontine or thalamic DMG, H3K27-altered. Patient tumours were segmented on preoperative brain magnetic resonance imaging (MRI) and mapped to a standard paediatric template (Extended Data Fig. 1a–c ). Tumour locations were compared between patients with short- and long-term overall survival using voxel-based lesion-symptom mapping (VLSM). Univariate VLSM across discovery cohort pontine and thalamic tumours identified a significant association between patient short-term survival and tumour pontine location (Extended Data Fig. 1d,e ), reflecting the known shorter overall survival of children with pontine versus thalamic DMG 2 . Aiming to identify specific voxels within the pons or thalamus associated with patient short- versus long-term survival, we performed separate univariate VLSM for pontine and thalamic tumour locations and multivariate VLSM across all tumour locations. Across both methods, no voxels associated with short-term survival were identified (Fig. 1b and Extended Data Fig. 1f–h ). To test for any prognostic impact of subthreshold VLSM results (defined as weak, non-significant voxelwise associations with short-term survival), we collected data from an independent cohort of children with primary pontine DMG/DIPG ( n  = 80) or…