Cancer-myeloid cell invasive program in pediatric-type diffuse high-grade glioma

Abstract

Pediatric-type diffuse high-grade gliomas (pHGGs) are aggressive, heterogeneous brain tumors shaped by intricate cancer-microenvironment cell-cell interactions. Here, we present an integrative multimodal pHGGmap, encompassing over 800,000 cells from 136 patients profiled across transcriptomic, epigenomic, and spatial modalities. Its analysis delineated robust cancer-myeloid cell programs that structured the tumor ecosystem and identified ten distinct cancer cell states, including previously unrecognized developmental and context-responsive programs. Among these, radial glial-like (RG-like) cells exhibited dual stress-adapted and infiltrative phenotypes. Tumor-associated monocyte-derived macrophages and resident microglia engaged in four distinct immunomodulatory programs aligned with specific cancer states. Three conserved multicellular communities were maintained across treatment, including a stable, spatially and transcriptionally linked RG-like/complement-macrophage niche, indicative of cellular co-option and adaptation to support invasion. Longitudinal profiling of a metastatic diffuse midline glioma case showed that RG-like cells predominate during dissemination and remain associated with complement-enriched macrophages, whose reprogramming restores immune activation. pHGGmap establishes a landmark resource for translational discovery. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=183 SRC="FIGDIR/small/701142v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@7ae699org.highwire.dtl.DTLVardef@b95b92org.highwire.dtl.DTLVardef@12adcf9org.highwire.dtl.DTLVardef@1118703_HPS_FORMAT_FIGEXP M_FIG C_FIG