Complexity-Informed Causal Modeling of Neurodevelopmental Trajectories in Pediatric High-Grade Gliomas: Divergences from Neural Stem Cell Signatures

TL;DR

This study uses complexity-informed causal modeling to understand the developmental and molecular mechanisms of pediatric high-grade gliomas, revealing disrupted neurodevelopmental pathways and identifying potential therapeutic targets.

Contribution

It introduces a novel complex systems approach to analyze gene expression and network complexity, uncovering molecular divergence and plasticity regulators in pediatric gliomas.

Findings

Shared developmental programs in gliomas and neural stem cells

Disrupted neurodevelopmental and signaling signatures in tumors

Potential biomarkers and therapeutic targets for glioma plasticity

Abstract

Pediatric high grade gliomas are lethal evolutionary disorders with stalled developmental trajectories and disrupted differentiation hierarchies. We integrate transcriptional and algorithmic network complexity based perturbation analysis to elucidate gene expression patterns and molecular divergence between Diffuse Midline Gliomas and glioblastoma, revealing shared developmental programs steering cell fate decision making. Our complex systems approach supports the emerging paradigm that pediatric high grade gliomas are neurodevelopmental disorders with hybrid lineage identities and disrupted patterning. We identify dysregulated neurodevelopmental and morphogenetic signatures, alongside bioelectric and neurotransmitter signaling programs that alter synaptic organization, neuronal fate commitment, and phenotypic plasticity, regulating glioma phenotypic switching. Causal drivers and regulators of plasticity were predicted as both biomarkers and therapeutic targets, reinforcing the view that pediatric gliomas are disorders of cell fate decisions and collective cellular identity. Decoded plasticity signatures indicate a teleonomic bias toward neural progenitor or neuron like identities, while synaptic transmission gene enrichment supports neuron glioma interactions shaping fate trajectories. These findings advance differentiation therapy as a systems medicine strategy, discovering plasticity regulators to reprogram malignant fates toward stable lineages, offering complex systems based targets for cancer reversion and predictive, preventive, precision oncology.