Clinician–scientists identify brain network linked to deadliest childhood brain cancer
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A human brain network associated with survival in children with diffuse midline glioma (DMG), the deadliest childhood brain cancer, has been identified by UCL clinician-scientists, raising the possibility of entirely new treatment approaches. The researchers found that DMG tumors seem to exploit the brain's existing neural circuitry to drive tumor growth and progression. Tumors that were more strongly connected to this network were associated with significantly shorter patient survival.
The study, published in Nature, builds on pioneering work in the field of cancer neuroscience, which shows that brain tumors, including DMG, dynamically interact with the otherwise healthy brain.
The study was led by Dr. Jai Sidpra and Dr. Valentina Lind, medical students enrolled in the MBPhD Program within the UCL Division of Medicine and senior author Professor Darren Hargrave's group at the UCL Great Ormond Street Institute of Child Health.
Working with collaborators from the U.K., Europe and the United States, the researchers provided the first evidence in humans that a conserved and clinically important human brain network underlies the progression of DMG, a devastating childhood brain cancer for which average survival remains approximately 12 months after diagnosis.
DMGs develop in the brainstem, thalamus and spinal cord—regions in the middle of the brain that are critical for consciousness, movement and breathing—making surgical removal impossible in most children. Existing treatments, including radiotherapy and chemotherapy, provide only temporary benefit and, despite decades of research, no curative treatments exist.
How tumors tap brain circuits
Over the past decade, pioneering laboratory studies led by collaborators at Stanford University have demonstrated that DMG actively integrates into otherwise healthy neural circuits through direct structural connections (synapses) and electrical signaling, as well as secreted (paracrine) factors in the tumor microenvironment. However, whether these tumor-brain interactions existed in humans, and whether they influenced patient survival, remained unknown.
Using imaging and clinical data from nearly 300 children with pontine and thalamic DMG across multiple international cohorts and clinical trials, the researchers worked with collaborators at the Harvard Center for Brain Circuit Therapeutics, Mass General Brigham, and Boston Children's Hospital (Boston, U.S.) to develop a method termed "tumor network mapping." Using a wiring diagram of the human brain (the "human connectome"), tumor network mapping enables researchers to look beyond individual tumor locations and map their connected brain circuitry.
This enabled them to identify a distributed pattern of brain functional connectivity, or "network," associated with tumor progression and patient survival. They found that tumors with stronger connectivity to a specific brain network were associated with substantially shorter overall survival, independent of standard clinical factors, including tumor location and treatment received. The researchers also demonstrated that tumor growth over time followed the architecture of this brain network, suggesting that DMG preferentially spread along connected neural circuits.
Some children with DMG undergo surgery to partially remove or obtain a sample of their tumor. Using generously donated patient tissue, investigators were able to perform genetic analyses that revealed fundamental biological differences between tumors with high and low connectivity to the DMG network.
Co-lead author Dr. Jai Sidpra (UCL Division of Medicine and UCL Great Ormond Street Institute of Child Health) said, "For the first time in patients, we have mapped the brain-wide connections important for tumor growth and survival between a brain tumor and the otherwise healthy brain. Importantly, we show that these connections relate to meaningful biological differences between tumors, which are known to promote the spread and integration of DMG throughout the brain's neural circuitry."
Collaborating authors Professor Michael Fox (Mass General Brigham and Harvard University) and Dr. Frederic Schaper (Mass General Brigham and Harvard University), whose work established the field of lesion network mapping, said, "This is an exciting extension of lesion network mapping, helping translate fundamental advances from the field of cancer neuroscience to human patients. We are grateful to be part of this multidisciplinary collaboration and are excited to investigate whether these findings extend to other tumor types, with the goal of maximizing their impact and benefit for patients."
Why timing in childhood matters
Crucially, the study sheds light on why DMG occurs at such characteristic ages in childhood yet is very rare in adults. By cross-referencing their findings with scans of normal brain development, the authors discovered that brain regions within the newly mapped DMG network undergo major metabolic transitions and maturation at two distinct periods that coincide with the peak ages at which children are diagnosed with DMG: early childhood and early adolescence.
Their data suggest that, as healthy childhood brain circuits naturally mature and come online, they navigate a neurodevelopmental window of vulnerability. During these critical periods, brain regions within the DMG network may be uniquely susceptible to DMG tumor initiation.
Potential routes to treatment
In a subgroup of children with thalamic DMG who underwent partial tumor removal, the researchers found preliminary evidence that removing highly connected tumor regions was associated with longer survival, regardless of the total tumor volume removed. These findings suggest that network disruption or modulation could be used as a future therapeutic strategy.
Co-lead author Dr. Valentina Lind (UCL Division of Medicine and UCL Great Ormond Street Institute of Child Health) said, "This raises the exciting possibility that treatments designed to target this circuit, including established neuromodulation technologies such as deep brain stimulation, could one day complement existing therapies. Planned clinical trials will be essential to determine whether such an approach is safe and effective for patients."
The researchers caution that further prospective studies are required before tumor network mapping can be used clinically to guide therapeutic interventions. These studies are due to start in late 2026.
Senior author Professor Darren Hargrave (UCL Great Ormond Street Institute of Child Health and a consultant neuro-oncologist at Great Ormond Street Hospital) said, "Diffuse midline glioma/Diffuse Intrinsic Pontine Glioma remains one of the most devastating diagnoses in childhood cancer and families urgently need new treatment options.
"This study provides an important framework for understanding how these tumors interact with the developing brain and opens up the possibility of new avenues for therapeutic investigation. While further work is needed before these findings can influence patient care, they represent a significant step forward in our understanding of this disease."
Collaborating author Professor Michelle Monje (Stanford University), a pioneer in the field of cancer neuroscience, said, "This is a landmark study for both the fields of pediatric neuro-oncology and cancer neuroscience. The work provides critical insights into the fundamental biology of this lethal childhood brain cancer, with important prognostic and treatment implications."
Publication details
Jai Sidpra et al, A prognostic human brain network for diffuse midline glioma, Nature (2026). DOI: 10.1038/s41586-026-10631-3
Journal information: Nature
Key medical concepts
Deep Brain StimulationTumor Microenvironment
Clinical categories
OncologyChildren's healthPediatricsNeurology Provided by University College London Who's behind this story?
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