Understanding the transcriptional heterogeneity of pediatric low-grade gliomas and its implication for tumor pathophysiology

Abstract

Pediatric low-grade gliomas (pLGGs) are the most common brain tumors of childhood and represent a clinically unique class of neoplasms. Although pLGGs display heterogeneous anatomical and histologic presentations, many exhibit indolent growth, prolonged periods of stability, and, in some cases, spontaneous growth arrest with increasing age. These features suggest that tumor behavior may be shaped by developmental context, yet the cellular and microenvironmental programs underlying pLGG biology remain incompletely defined. To better understand the cellular behaviors of this heterogenous group of tumors, we have employed single-cell and single-nucleus RNA sequencing technologies to analyze a large-scale dataset (>300,000 cells and nuclei) of 54 pLGGs across many histological subtypes. pLGGs exhibited a conserved cellular architecture dominated by oligodendrocyte precursor cells and other immature glial populations, accompanied by substantial immune infiltration primarily composed of myeloid cells. Across tumors, transcriptional programs diverged from postnatal normal brain but partially aligned with fetal-like developmental states, indicating arrested or reversed maturation. Comparative analyses across tumor subtypes, ages, and locations revealed systematic differences in cellular composition, inflammatory and proliferative signaling states, and cell-cell communication networks. Age-stratified receptor-ligand analyses identified pediatric-enriched microenvironmental signals shared between tumors and developing brain, alongside adult-emergent neuronal signals absent from pLGGs that may constrain tumor growth. These findings identify pLGGs as developmentally constrained tumors that persist through exploitation of pediatric brain microenvironmental programs, offering a biological framework for their age-restricted incidence and clinical behavior.