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| Status |
Public on Oct 06, 2023 |
| Title |
Mouse methylation array of glioblastoma mGB2 cells |
| Organism |
Mus musculus |
| Experiment type |
Methylation profiling by array
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| Summary |
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) is a metabolic enzyme that converts branched-chain amino acids into branched-chain keto acids, depleting cellular α-ketoglutarate and producing glutamate. BCAT1 was shown to drive the growth of glioblastoma and other cancers; however, its oncogenic mechanism remains poorly understood. 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 TET 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. In summary, 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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| Overall design |
DNA was extracted from cultured mGB2 cells. Samples unclude the control cells (NT), Bcat1-knockout cells (BKO) and Bcat1-KO cells expressing shRNA targeting Tet1 (shTet1) or Tet2 (shTet2). Each sample was present in triplicates
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| Web link |
http://10.1093/neuonc/noad190
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| Contributor(s) |
Boskovic P, Wilke N, Man K, Lichter P, Francois L, Radlwimmer B |
| Citation(s) |
37769206 |
| |
| Submission date |
Oct 06, 2023 |
| Last update date |
Oct 07, 2023 |
| Contact name |
Pavle Boskovic |
| E-mail(s) |
pavle@wustl.edu
|
| Organization name |
Washington University in Saint Louis
|
| Street address |
4515 McKinley Ave
|
| City |
Saint Louis |
| State/province |
MO |
| ZIP/Postal code |
63110 |
| Country |
USA |
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| Platforms (1) |
| GPL32685 |
Illumina Infinium MouseMethylation array (MouseMethylation-12v1-0_A2) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA1024968 |
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