Glioblastoma cell fate is differentially regulated by the microenvironments of the tumor bulk and infiltrative margin

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• dc.contributor.author Garcia-Diaz, Claudia
• dc.contributor.author Pöysti, Anni
• dc.contributor.author Mereu, Elisabetta
• dc.contributor.author Clements, Melanie P.
• dc.contributor.author Brooks, Lucy J.
• dc.contributor.author Galvez-Cancino, Felipe
• dc.contributor.author Castillo, Simon P.
• dc.contributor.author Tang, Wenhao
• dc.contributor.author Beattie, Gordon
• dc.contributor.author Courtot, Lilas
• dc.contributor.author Ruiz, Sara
• dc.contributor.author Roncaroli, Federico
• dc.contributor.author Yuan, Yinyin
• dc.contributor.author Marguerat, Samuel
• dc.contributor.author Quezada, Sergio A.
• dc.contributor.author Heyn, Holger
• dc.contributor.author Parrinello, Simona
• dc.date.accessioned 2023-06-20T06:24:44Z
• dc.date.available 2023-06-20T06:24:44Z
• dc.date.issued 2023
• dc.description.abstract Glioblastoma (GBM) recurrence originates from invasive margin cells that escape surgical debulking, but to what extent these cells resemble their bulk counterparts remains unclear. Here, we generated three immunocompetent somatic GBM mouse models, driven by subtype-associated mutations, to compare matched bulk and margin cells. We find that, regardless of mutations, tumors converge on common sets of neural-like cellular states. However, bulk and margin have distinct biology. Injury-like programs associated with immune infiltration dominate in the bulk, leading to the generation of lowly proliferative injured neural progenitor-like cells (iNPCs). iNPCs account for a significant proportion of dormant GBM cells and are induced by interferon signaling within T cell niches. In contrast, developmental-like trajectories are favored within the immune-cold margin microenvironment resulting in differentiation toward invasive astrocyte-like cells. These findings suggest that the regional tumor microenvironment dominantly controls GBM cell fate and biological vulnerabilities identified in the bulk may not extend to the margin residuum.
• dc.description.sponsorship This work was funded by Cancer Research UK (C55501/A21203, C555011/A22572, C25858/A28592), the Cancer Research UK City of London Centre Award (C7893/A26233), the Radiation Research Unit at the Cancer Research UK City of London Centre Award (C7893/A28990), the NIHR Biomedical Research Centre (BRC507/CN/SP/101330), the Oli Hilsdon Foundation through The Brain Tumour Charity (GN-000595), the MCIN (PID2020-115439GB-I00), and the Fundació la Marató de TV3 (772/C/2019). We thank A. Berns for Cdkn2a−/− mice, M. Aguet for Ifnar1−/− and Ifnar1−/−;Ifngr1−/− mice, P. Salomoni and S. Pollard for constructs, B. Antolin-Fontes for cloning, G. Rodriguez-Esteban for bioinformatics, M. Pathania for technical advice, A. Flanagan for histopathological advice, J. Manji for microscopy, and Y. Guo, G. Morrow, and B. Wilbourn for FACS. Graphical abstract and Figure 2L were created with BioRender.com.
• dc.format.mimetype application/pdf
• dc.identifier.citation Garcia-Diaz C, Pöysti A, Mereu E, Clements MP, Brooks LJ, Galvez-Cancino F, Castillo SP, Tang W, Beattie G, Courtot L, Ruiz S, Roncaroli F, Yuan Y, Marguerat S, Quezada SA, Heyn H, Parrinello S. Glioblastoma cell fate is differentially regulated by the microenvironments of the tumor bulk and infiltrative margin. Cell Rep. 2023 May 30;42(5):112472. DOI: 10.1016/j.celrep.2023.112472
• dc.identifier.doi http://dx.doi.org/10.1016/j.celrep.2023.112472
• dc.identifier.issn 2211-1247
• dc.identifier.uri http://hdl.handle.net/10230/57258
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Cell Rep. 2023 May 30;42(5):112472
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-115439GB-I00
• dc.rights © 2023 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword CP: Cancer
• dc.subject.keyword Dormancy
• dc.subject.keyword Glioblastoma
• dc.subject.keyword Invasion
• dc.subject.keyword Somatic mouse models
• dc.subject.keyword Tumor margin
• dc.subject.keyword Tumor microenvironment
• dc.title Glioblastoma cell fate is differentially regulated by the microenvironments of the tumor bulk and infiltrative margin
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion