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

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100 1 _ |a Bessler, Nils
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245 _ _ |a De novo H3.3K27M-altered diffuse midline glioma in human brainstem organoids to dissect GD2 CAR T cell function.
260 _ _ |a London
|c 2026
|b Nature Research
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520 _ _ |a 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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700 1 _ |a Wezenaar, Amber K L
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700 1 _ |a Ariese, Hendrikus C R
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700 1 _ |a Honhoff, Celina
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700 1 _ |a Dommann, Noëlle
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700 1 _ |a Wehrens, Ellen J
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700 1 _ |a Ruiz Moreno, Cristian
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700 1 _ |a van den Broek, Thijs J M
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700 1 _ |a Collot, Raphaël V U
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700 1 _ |a Kloosterman, Daan J
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700 1 _ |a Keramati, Farid
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700 1 _ |a Roosen, Mieke
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700 1 _ |a de Blank, Sam
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700 1 _ |a van Vliet, Esmée
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700 1 _ |a Barrera Román, Mario
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700 1 _ |a Gatti, Lucrezia C D E
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700 1 _ |a Ertürk, Ali
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700 1 _ |a Kuball, Jürgen
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700 1 _ |a Sebestyén, Zsolt
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700 1 _ |a Patrizi, Sara
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700 1 _ |a Miele, Evelina
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700 1 _ |a Künkele, Annette
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700 1 _ |a Kranendonk, Mariëtte E G
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700 1 _ |a Cornel, Annelisa M
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700 1 _ |a Nierkens, Stefan
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700 1 _ |a Mayer, Christian
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700 1 _ |a Stunnenberg, Hendrik G
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700 1 _ |a Alemany, Anna
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700 1 _ |a Alieva, Maria
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700 1 _ |a Rios, Anne C
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