Multidimensional profiling of tumor cell heterogeneity reveals cell-lineage specific functions in supratentorial ependymomas

Abstract

Supratentorial ependymomas (ST-EPNs) are aggressive pediatric brain tumors categorized into distinct molecular subgroups. Despite their proposed origin from radial glia cells, the comparative analysis of tumor cell states across these subgroups remains critically understudied. In this study, we integrate molecular cell states, spatial architecture, and cell migration patterns of a comprehensive cohort of ST-EPNs to delineate the molecular and functional features of aberrant differentiation at single-cell resolution. Our findings reveal that while all supratentorial ependymomas display signatures of temporally restricted neuroepithelial cells, subgroups of ST-EPN exhibit diverse differentiation potential associated with neural or ependymal differentiation. Additionally, we elucidate the global spatial localization of cell states and unveil a higher-order structural tumor organization driven by the presence of the mesenchymal tumor cell state. By benchmarking a morpho-molecular cell-state classification system across various disease models, we demonstrate that molecularly defined cell states exhibit distinct architecture of neurite-like extensions and migration patterns. Collectively, our study presents a multilayered framework for investigating ST-EPN cellular states, offering potential therapeutic implications.