Branched-chain amino acid transaminase 1 regulates glioblastoma cell plasticity and contributes to immunosuppression
Glioblastoma is the most common malignant brain tumor in adults. Cellular plasticity and the poorly differentiated features result in a fast relapse of the tumors following treatment. Moreover, the immunosuppressive microenvironment proved to be a major obstacle to immunotherapeutic approaches. Bran...
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| Hauptverfasser: | , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
February 2024
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| Ausgabe: | Early view |
| In: |
Neuro-Oncology
Year: 2024, Jahrgang: 26, Heft: 2, Pages: 251-265 |
| ISSN: | 1523-5866 |
| DOI: | 10.1093/neuonc/noad190 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1093/neuonc/noad190
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| Verfasserangaben: | Pavle Boskovic, Nathalie Wilke, Ka-Hou Man, Peter Lichter, Liliana Francois, and Bernhard Radlwimmer |
| Zusammenfassung: | Glioblastoma is the most common malignant brain tumor in adults. Cellular plasticity and the poorly differentiated features result in a fast relapse of the tumors following treatment. Moreover, the immunosuppressive microenvironment proved to be a major obstacle to immunotherapeutic approaches. Branched-chain amino acid transaminase 1 (BCAT1) was shown to drive the growth of glioblastoma and other cancers;however, its oncogenic mechanism remains poorly understood.Using human tumor data, cell line models and orthotopic immuno-competent and -deficient mouse models, we investigated the phenotypic and mechanistic effects of BCAT1 on glioblastoma cell state and immunomodulation.Here, we show that BCAT1 is crucial for maintaining the poorly differentiated state of glioblastoma cells and that its low expression correlates with a more differentiated glioblastoma phenotype. Furthermore, orthotopic tumor injection into immunocompetent mice demonstrated that the brain microenvironment is sufficient to induce differentiation of Bcat1-KO tumors in vivo. We link the transition to a differentiated cell state to the increased activity of ten-eleven translocation demethylases and the hypomethylation and activation of neuronal differentiation genes. In addition, the knockout of Bcat1 attenuated immunosuppression, allowing for an extensive infiltration of CD8+ cytotoxic T-cells and complete abrogation of tumor growth. Further analysis in immunodeficient mice revealed that both tumor cell differentiation and immunomodulation following BCAT1-KO contribute to the long-term suppression of tumor growth.Our study unveils BCAT1’s pivotal role in promoting glioblastoma growth by inhibiting tumor cell differentiation and sustaining an immunosuppressive milieu. These findings offer a novel therapeutic avenue for targeting glioblastoma through the inhibition of BCAT1. |
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| Beschreibung: | Veröffentlicht: 28 September 2023 Gesehen am 18.12.2023 |
| Beschreibung: | Online Resource |
| ISSN: | 1523-5866 |
| DOI: | 10.1093/neuonc/noad190 |