Multidimensional profiling of heterogeneity in supratentorial ependymomas

Supratentorial ependymomas are aggressive childhood brain cancers that retain features of neurodevelopmental cell types<sup>1</sup> and segregate into molecularly and clinically distinct subgroups<sup>2,3</sup>, suggesting different developmental roots. The developmental signatures, as well as microenvironmental factors, underlying aberrant cellular transformation and behaviour across each supratentorial ependymoma subgroup are unclear. Here we integrated single-cell and spatial transcriptomics, as well as in vitro and in vivo live-cell imaging, to define supratentorial ependymoma cell states, spatial organization and dynamic behaviour within the neural microenvironment. We find that individual tumour subgroups have two distinct progenitor-like cell states-neuroepithelial-like and embryonic-like-that are reminiscent of early human brain development and diverge in the extent of their neuronal or ependymal differentiation. We further identify several modes of spatial organization of these tumours, including a high-order architecture that is influenced by mesenchymal and hypoxia signatures, and local neighbourhood structures. Finally, we identify a role for brain-resident cells in shifting supratentorial ependymoma cellular heterogeneity towards neuronal-like cells that co-opt immature neuronal morphology and migratory mechanisms, and a subset of neuroepithelial-like cells that are both proliferative and highly migratory. Collectively, these findings provide a multidimensional framework to integrate transcriptional and phenotypic characterization of tumour heterogeneity in supratentorial ependymoma and its potential clinical implications.

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Journal
Nature
Published
2026-03-11
DOI
https://doi.org/10.1038/s41586-026-10214-2
Primary Topic
Glioma Diagnosis and Treatment
Type
article
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article

Multidimensional profiling of heterogeneity in supratentorial ependymomas

Mariella G. Filbin, Kristian W. Pajtler, Ekin Reyhan, Sanda Alexandrescu et al.
Nature
Glioma Diagnosis and Treatment
article

Multidimensional profiling of heterogeneity in supratentorial ependymomas

Mariella G. Filbin, Kristian W. Pajtler, Ekin Reyhan, Sanda Alexandrescu, Costanza Lo Cascio, Gustavo Alencastro Veiga Cruzeiro, David R. Ghasemi, Daeun Jeong, Johannes Gojo, Sara G. Danielli, Lan Jiang, Matthew Mullally, Bernhard Englinger, Katharina Bruckner, Shashank P. Katiyar, Olivia A. Hack, Andrezza Nascimento, Jacob S Rozowsky, Julia K. Sundheimer, Lissa Catherine Baird, Sina Neyazi, Varun Venkataramani, Sophia Castellani, Carlos Alberto Oliveira de Biagi-Junior, Daniela Lötsch-Gojo, Marcel Kool, Stefan M. Pfister, Marc Philipp Dehler, Maria Pazyra-Murphy, Rebecca D. Haase, Alicia-Christina Baumgartner, Andrey Korshunov, Cuong M. Nguyen, McKenzie L. Shaw, Tomasz J. Nowakowski, Kendra K. Maaß, Joana G. Marques, Elsa Couvillon, Svenja K. Tetzlaff
article en

Abstract

Supratentorial ependymomas are aggressive childhood brain cancers that retain features of neurodevelopmental cell types<sup>1</sup> and segregate into molecularly and clinically distinct subgroups<sup>2,3</sup>, suggesting different developmental roots. The developmental signatures, as well as microenvironmental factors, underlying aberrant cellular transformation and behaviour across each supratentorial ependymoma subgroup are unclear. Here we integrated single-cell and spatial transcriptomics, as well as in vitro and in vivo live-cell imaging, to define supratentorial ependymoma cell states, spatial organization and dynamic behaviour within the neural microenvironment. We find that individual tumour subgroups have two distinct progenitor-like cell states-neuroepithelial-like and embryonic-like-that are reminiscent of early human brain development and diverge in the extent of their neuronal or ependymal differentiation. We further identify several modes of spatial organization of these tumours, including a high-order architecture that is influenced by mesenchymal and hypoxia signatures, and local neighbourhood structures. Finally, we identify a role for brain-resident cells in shifting supratentorial ependymoma cellular heterogeneity towards neuronal-like cells that co-opt immature neuronal morphology and migratory mechanisms, and a subset of neuroepithelial-like cells that are both proliferative and highly migratory. Collectively, these findings provide a multidimensional framework to integrate transcriptional and phenotypic characterization of tumour heterogeneity in supratentorial ependymoma and its potential clinical implications.

Nature
Broad Institute (US), Boston Children's Hospital (US), Universität Hamburg (DE), German Cancer Research Center (DE), University of California, San Francisco (US), Heidelberg University (DE), University Hospital Heidelberg (DE), University Medical Center Utrecht (NL), Comprehensive Cancer Center Vienna (AT), University Medical Center Hamburg-Eppendorf (DE), Kinderkrebs-Zentrum Hamburg (DE), National Center for Tumor Diseases (DE), Hopp Children's Cancer Center Heidelberg (DE), Princess Máxima Center (NL), Neurological Surgery (US), Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US), Medical University of Vienna (AT)
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Glioma Diagnosis and Treatment
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