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Bessler, N.* ; Wezenaar, A.K.L.* ; Ariese, H.C.R.* ; Honhoff, C.* ; Dommann, N.* ; Wehrens, E.J.* ; Ruiz Moreno, C.* ; van den Broek, T.J.M.* ; Collot, R.V.U.* ; Kloosterman, D.J.* ; Keramati, F.* ; Roosen, M.* ; de Blank, S.* ; van Vliet, E.* ; Barrera Román, M.* ; Gatti, L.C.D.E.* ; Ertürk, A. ; Kuball, J.* ; Sebestyén, Z.* ; Kool, M.* ; Patrizi, S.* ; Miele, E.* ; Künkele, A.* ; Kranendonk, M.E.G.* ; Cornel, A.M.* ; Nierkens, S.* ; Mayer, C.* ; Stunnenberg, H.G.* ; Alemany, A.* ; Alieva, M.* ; Rios, A.C.*

De novo H3.3K27M-altered diffuse midline glioma in human brainstem organoids to dissect GD2 CAR T cell function.

Nat. Cancer, DOI: 10.1038/s43018-025-01084-0 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Diffuse midline glioma (DMG) is a highly aggressive and untreatable pediatric cancer primarily arising in the pontine brainstem region, necessitating the development of representative models for treatment advance. Here we developed an FGF4-driven human brainstem organoid model, which we used to genetically engineer H3.3K27M-altered DMG. We demonstrated that brainstem pontine glial specification is critical for DMG tumorigenesis, yielding infiltrative tumors that recapitulate patient-representative intratumoral heterogeneity. Prolonged GD2 chimeric antigen receptor (CAR) T cell treatment mirrored clinical outcomes and revealed extensive transcriptional heterogeneity, from which both potent effector and dysfunctional CAR T cell populations could be identified. Furthermore, incorporation of myeloid cells generated DMG-specific microglia that reduced treatment efficacy and revealed CAR T cell functional states most vulnerable to microglia-mediated immunosuppression. Thus, we present a representative DMG model offering a months-long experimental window in vitro, which we leveraged to delineate CAR T cell functionality and microglial impact, aiding therapy development for this devastating disease.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Central-nervous-system; Histone H3.3; High-grade; Tissue; Classification; Generation; Programs; Culture; Genes
ISSN (print) / ISBN 2662-1347
e-ISSN 2662-1347
Zeitschrift Nature Cancer
Verlag Springer
Verlagsort Heidelberger Platz 3, Berlin, 14197, Germany
Begutachtungsstatus Peer reviewed
Institut(e) Institute for Intelligent Biotechnologies (IBIO)
Förderungen European Research Council ERC starting grant Reference: 804412
Stichting Proefdiervrij