MYC-dependent upregulation of the de novo serine and glycine synthesis pathway is a targetable metabolic vulnerability in group 3 medulloblastoma.

Autor:	Adiamah M; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle Upon Tyne, UK., Poole B; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle Upon Tyne, UK., Lindsey JC; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle Upon Tyne, UK., Kohe S; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK., Morcavallo A; Division of Clinical Studies, Institute of Cancer Research (ICR), London and Royal Marsden NHS Trust, Sutton, UK., Burté F; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle Upon Tyne, UK., Hill RM; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle Upon Tyne, UK., Blair H; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle Upon Tyne, UK., Thompson D; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle Upon Tyne, UK., Singh M; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle Upon Tyne, UK., Swartz S; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle Upon Tyne, UK., Crosier S; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle Upon Tyne, UK., Zhang T; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Maddocks ODK; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Peet A; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK., Chesler L; Division of Clinical Studies, Institute of Cancer Research (ICR), London and Royal Marsden NHS Trust, Sutton, UK., Hickson I; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle Upon Tyne, UK., Maxwell RJ; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle Upon Tyne, UK., Clifford SC; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle Upon Tyne, UK.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2024 Oct 08. Date of Electronic Publication: 2024 Oct 08.
DOI:	10.1093/neuonc/noae179
Abstrakt:	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. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
Databáze:	MEDLINE
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