第 3 组髓母细胞瘤 (MBGRP3) 约占髓母细胞瘤的 25%，与 c-MYC (MYC) 扩增密切相关，这会显着降低患者的生存率。尽管 MYC 表达升高是 MBGRP3 的一个重要分子特征，但直接靶向 MYC 仍然难以捉摸，需要替代策略。 MYC 驱动的 MBGRP3 的代谢格局在很大程度上尚未被探索，可能为治疗提供新的机会。为了研究 MYC 诱导的 MBGRP3 代谢改变，我们在基于等基因细胞的模型系统中耗尽了 MYC，然后进行 1H 高分辨率魔角光谱(HRMAS) 和稳定同位素解析代谢组学，以评估细胞内代谢物和途径动力学的变化。稳态代谢分析揭示了参与一碳代谢（如甘氨酸）的代谢物中一致的 MYC 依赖性变化。 13C-葡萄糖追踪进一步揭示了 MYC 敲低后葡萄糖衍生的丝氨酸和甘氨酸（从头合成）的减少，这与磷酸甘油酸脱氢酶（PHGDH）（该途径中的限速酶）的表达和活性降低相一致。此外，与低表达的细胞相比，MYC 过表达的 MBGRP3 细胞更容易受到 PHGDH 的药理学抑制。使用体内荷瘤基因工程和异种移植小鼠模型，PHGDH 的药理学抑制可增加存活率，表明丝氨酸/甘氨酸从头合成途径是维持肿瘤进展的促存活机制。重要的是，在原发性人髓母细胞瘤中，PHGDH 表达增加与 MYC 扩增和较差的临床结果密切相关。我们的研究结果支持 MYC 诱导的 MBGRP3 中丝氨酸/甘氨酸途径的依赖性，这代表了这种预后不良疾病组的新治疗策略.© 作者 2024。由牛津大学出版社代表神经肿瘤学会出版。

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.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.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.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.