PuSH - Publication Server of Helmholtz Zentrum München

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)
Publ. Version/Full Text Research data 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.
Altmetric
Additional Metrics?
[➜Log in]
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Keywords Central-nervous-system; Histone H3.3; High-grade; Tissue; Classification; Generation; Programs; Culture; Genes
ISSN (print) / ISBN 2662-1347
e-ISSN 2662-1347
Journal Nature Cancer
Publisher Springer
Publishing Place Heidelberger Platz 3, Berlin, 14197, Germany
Reviewing status Peer reviewed
Institute(s) Institute for Intelligent Biotechnologies (IBIO)
Grants European Research Council ERC starting grant Reference: 804412
Stichting Proefdiervrij