UNRAVELLING THE ROLE OF NEURAL PROGENITOR CELLS IN THE DEVELOPMENT OF PAEDIATRIC HIGH-GRADE GLIOMA

Paediatric high-grade gliomas (pHGGs) are aggressive brain tumours with dismal prognosis and limited therapeutic options. Unlike adult gliomas, pHGGs occur during active brain development when neurogenesis is extensive and neural progenitor cells (NPCs) maintain high proliferative capacity. While adult glioblastomas near the subventricular zone show worse outcomes, the functional contribution of NPC-tumour interactions in paediatric cases remains unexplored, representing a critical knowledge gap in understanding pHGG biology.
We investigated NPC signalling effects on patient-derived pHGG cultures through functional assays with NPC-conditioned medium, which significantly enhanced pHGG proliferation across multiple subtypes. Secretome analysis revealed G34R mutant cells uniquely secreted neural stem cell markers (FABP7, ALDH1A1), axonal growth factors (GAP43, PTN), and synaptic scaffolding proteins, creating a multi-lineage neural developmental niche absent in normal astrocytes. RNA sequencing revealed distinct transcriptomic responses: G34R mutant tumours underwent neuralization, upregulating neuronal markers and synaptic remodelling genes alongside forebrain development pathways, while K27M mutant tumours showed activation of distinct cell proliferation programs.
We established dual-labelled tumour–NPC co-culture organoid systems, revealing reciprocal Ki67 activation in both G34R tumour cells and NPCs, confirming bi-directional growth effects. Consistent with this, secretome analysis confirmed that G34R cells secrete functional stemness proteins and growth factors, mechanistically supporting tumour-mediated NPC proliferation.
This study provides first evidence of NPC-pHGG interactions through both secreted signalling and direct cell contact, revealing subtype-specific developmental mechanisms and offering novel therapeutic targets for these devastating tumours.