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Spatial transcriptomic analysis delineates epithelial and mesenchymal subpopulations and transition stages in childhood ependymoma

Fu, Rui; Norris, Gregory A; Willard, Nicholas; Griesinger, Andrea M; Riemondy, Kent A; Amani, Vladimir; Grimaldo, Enrique; Harris, Faith; Hankinson, Todd C; Mitra, Siddhartha; Ritzmann, Timothy A; Grundy, Richard R; Foreman, Nicholas K; Donson, Andrew M

Spatial transcriptomic analysis delineates epithelial and mesenchymal subpopulations and transition stages in childhood ependymoma Thumbnail


Authors

Rui Fu

Gregory A Norris

Nicholas Willard

Andrea M Griesinger

Kent A Riemondy

Vladimir Amani

Enrique Grimaldo

Faith Harris

Todd C Hankinson

Siddhartha Mitra

RICHARD GRUNDY richard.grundy@nottingham.ac.uk
Professor of Paediatric Neuro-Oncology

Nicholas K Foreman

Andrew M Donson



Abstract

Background The diverse cellular constituents of childhood brain tumor ependymoma, recently revealed by single cell RNA-sequencing, may underly therapeutic resistance. Here we use spatial transcriptomics to further advance our understanding of the tumor microenvironment, mapping cellular subpopulations to the tumor architecture of ependymoma posterior fossa subgroup A (PFA), the commonest and most deadly childhood ependymoma variant. Methods Spatial transcriptomics data from intact PFA sections was deconvoluted to resolve the histological arrangement of neoplastic and non-neoplastic cell types. Key findings were validated using immunohistochemistry, in vitro functional assays and outcome analysis in clinically-annotated PFA bulk transcriptomic data. Results PFA are comprised of epithelial and mesenchymal histological zones containing a diversity of cellular states, each zone including co-existing and spatially distinct undifferentiated progenitor-like cells; a quiescent mesenchymal zone population, and a second highly mitotic progenitor population that is restricted to hypercellular epithelial zones and that is more abundant in progressive tumors. We show that myeloid cell interaction is the leading cause of mesenchymal transition in PFA, occurring in zones spatially distinct from hypoxia-induced mesenchymal transition, and these distinct EMT-initiating processes were replicated using in vitro models of PFA. Conclusions These insights demonstrate the utility of spatial transcriptomics to advance our understanding of ependymoma biology, revealing a clearer picture of the cellular constituents of PFA, their interactions and influence on tumor progression.

Citation

Fu, R., Norris, G. A., Willard, N., Griesinger, A. M., Riemondy, K. A., Amani, V., …Donson, A. M. (2023). Spatial transcriptomic analysis delineates epithelial and mesenchymal subpopulations and transition stages in childhood ependymoma. Neuro-Oncology, 25(4), 786-798. https://doi.org/10.1093/neuonc/noac219

Journal Article Type Article
Acceptance Date Sep 13, 2022
Online Publication Date Oct 10, 2022
Publication Date Apr 6, 2023
Deposit Date Oct 11, 2022
Publicly Available Date Oct 11, 2023
Journal Neuro-Oncology
Print ISSN 1522-8517
Electronic ISSN 1523-5866
Publisher Oxford University Press (OUP)
Peer Reviewed Peer Reviewed
Volume 25
Issue 4
Pages 786-798
DOI https://doi.org/10.1093/neuonc/noac219
Keywords Cancer Research; Neurology (clinical); Oncology
Public URL https://nottingham-repository.worktribe.com/output/12322881
Publisher URL https://academic.oup.com/neuro-oncology/advance-article-abstract/doi/10.1093/neuonc/noac219/6755445?redirectedFrom=fulltext&login=false

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