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Lookup NU author(s): Magretta Adiamah, Beth Poole, Dr Janet Lindsey, Dr Rebecca Hill, Dr Helen Blair, Dr Dean Thompson, Mankaran Singh, Shanel Swartz, Dr Stephen Crosier, Professor Ian HicksonORCiD, Professor Steven CliffordORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. Background. Group 3 medulloblastoma (MBGRP3) represents around 25% of medulloblastomas and is strongly associated with c-MYC (MYC) amplification, which confers significantly worse patient survival. Although elevated MYC expression is a significant molecular feature in MBGRP3, direct targeting of MYC remains elusive, and alternative strategies are needed. The metabolic landscape of MYC-driven MBGRP3 is largely unexplored and may offer novel opportunities for therapies. Methods. To study MYC-induced metabolic alterations in MBGRP3, we depleted MYC in isogenic cell-based model systems, followed by 1H high-resolution magic-angle spectroscopy (HRMAS) and stable isotope-resolved metabolomics, to assess changes in intracellular metabolites and pathway dynamics. Results. Steady-state metabolic profiling revealed consistent MYC-dependent alterations in metabolites involved in one-carbon metabolism such as glycine.13C-glucose tracing further revealed a reduction in glucose-derived serine and glycine (de novo synthesis) following MYC knockdown, which coincided with lower expression and activity of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in this pathway. Furthermore, MYC-overexpressing MBGRP3 cells were more vulnerable to pharmacological inhibition of PHGDH compared to those with low expression. Using in vivo tumor-bearing genetically engineered and xenograft mouse models, pharmacological inhibition of PHGDH increased survival, implicating the de novo serine/glycine synthesis pathway as a pro-survival mechanism sustaining tumor progression. Critically, in primary human medulloblastomas, increased PHGDH expression correlated strongly with both MYC amplification and poorer clinical outcomes. Conclusions. Our findings support a MYC-induced dependency on the serine/glycine pathway in MBGRP3 that represents a novel therapeutic treatment strategy for this poor prognosis disease group.
Author(s): Adiamah M, Poole B, Lindsey JC, Kohe S, Morcavallo A, Burte F, Hill RM, Blair H, Thompson D, Singh M, Swartz S, Crosier S, Zhang T, Maddocks ODK, Peet A, Chesler L, Hickson I, Maxwell RJ, Clifford SC
Publication type: Article
Publication status: Published
Journal: Neuro-Oncology
Year: 2025
Volume: 27
Issue: 1
Pages: 237-253
Print publication date: 01/01/2025
Online publication date: 08/10/2024
Acceptance date: 02/04/2018
Date deposited: 27/01/2025
ISSN (print): 1522-8517
ISSN (electronic): 1523-5866
Publisher: Oxford University Press
URL: https://doi.org/10.1093/neuonc/noae179
DOI: 10.1093/neuonc/noae179
Data Access Statement: The data will be made available upon reasonable request to the corresponding author.
PubMed id: 39377369
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