Glioma and ependymoma through the lens of brain development, stem cells, and plasticity.

Abstract

Brain tumors are increasingly understood as having components of a development organization in which malignant cells leverage neural progenitor programs, lineage hierarchies, and circuit interactions that normally shape the developing brain. This review examines how these principles inform the biology of ependymoma and gliomas across the age spectrum, including H3 K27-altered diffuse midline glioma, H3 G34-mutant diffuse hemispheric glioma, IDH-mutant glioma, and glioblastoma. We highlight how tumor identity reflects developmental timing, regional context, and cell-of-origin competence, while also emphasizing that malignant cells can acquire plasticity beyond their normal counterparts. Across entities, single-cell, spatial, lineage-tracing, and organoid studies reveal progenitor-like compartments that sustain tumor growth, generate heterogeneous malignant states, and interact dynamically with the neural and immune microenvironment. Cancer neuroscience further extends this developmental framework by showing that neuronal activity, synaptic input, and neuromodulatory signaling can regulate tumor proliferation, migration, epigenetic state, and therapeutic response. Together, these findings argue that brain tumors should be viewed not as disorganized cellular masses but as aberrant developmental systems. Defining the developmental dependencies and circuit vulnerabilities of malignant progenitor states may enable more precise therapies that target tumor biology while preserving essential brain function.