Decoding Epileptogenic Glioma Networks Using Forebrain Assembloids

Objetivo

Pediatric-type diffuse high-grade gliomas are the primary cause of cancer-related mortality in children and adolescents. The most common and aggressive forms harbor mutually exclusive mutations in histone 3 (H3), involving distinct brain regions and developmental origins. In contrast to other gliomas, GABAergic interneuron progenitors are implicated as the cells of origin for H3G34-mutant diffuse hemispheric gliomas (DHGs), which almost exclusively affect the cerebral hemispheres.

Seizures are a common comorbidity in patients with cortical gliomas, with evidence suggesting that gliomas alter synaptic structures to induce hyperexcitability. Neuronal activity, in turn, accelerates glioma progression through paracrine signaling and neuron-to-glioma synapses. Despite their cortical involvement, high seizure incidence, and poor prognosis, neuron-glioma interactions in DHGs remain understudied.

Human cerebral organoids, pioneered by the Knoblich Lab, recapitulate early brain architecture and circuit assembly via excitatory neurogenesis (dorsal forebrain) and interneuron development (ventral forebrain). Ultimately leading to functional network activity with complex oscillatory dynamics, organoids provide the ideal platform to study brain tumors in the context of network pathologies.

In this project, I will develop patient-derived models of seizure-associated DHGs in brain region specific cerebral organoids to examine neuron-glioma synapses. Using barcoded viral tracing and genetic perturbation screening, I will identify synaptic interaction partners and tumor-specific anti-connectivity targets. Electrophysiological recordings will assess the effects of anti-epileptogenic and anti-tumorigenic perturbations. This work will provide critical insights into neuron-glioma communication and its role in epileptogenesis during tumor progression, with important therapeutic implications.

Ámbito científico (EuroSciVoc)

CORDIS clasifica los proyectos con EuroSciVoc, una taxonomía plurilingüe de ámbitos científicos, mediante un proceso semiautomático basado en técnicas de procesamiento del lenguaje natural. La clasificación de este proyecto ha sido validada por su equipo.

• ciencias médicas y de la saludmedicina clínicaoncología
• ciencias naturalesciencias biológicasbiología molecularneurociencia molecular

Palabras clave

• Brain Organoids
• Brain Tumors
• Pediatric Glioma
• Cancer
• Neuronal Connectivity
• Neural Networks
• Synaptic Tracing
• CRISPR-screening
• Epileptogenesis
• Seizure Activity
• Epilepsy
• Electrophysiology

Programa(s)

• HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme

Tema(s)

• HORIZON-MSCA-2024-PF-01-01 - MSCA Postdoctoral Fellowships 2024

Convocatoria de propuestas

(se abrirá en una nueva ventana) HORIZON-MSCA-2024-PF-01

Régimen de financiación

Coordinador