Adiamah Magretta, Poole Bethany, Lindsey Janet C, Kohe Sarah, Morcavallo Alaide, Burté Florence, Hill Rebecca M, Blair Helen, Thompson Dean, Singh Mankaran, Swartz Shanel, Crosier Stephen, Zhang Tong, Maddocks Oliver D K, Peet Andrew, Chesler Louis, Hickson Ian, Maxwell Ross J, Clifford Steven C
Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle Upon Tyne, UK.
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
Neuro Oncol. 2025 Jan 12;27(1):237-253. doi: 10.1093/neuonc/noae179.
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.
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，这会导致患者生存率显著降低。虽然MYC表达升高是MBGRP3的一个重要分子特征，但直接靶向MYC仍然难以实现，因此需要其他策略。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，我们在同基因细胞模型系统中敲低MYC，随后进行1H高分辨率魔角光谱（HRMAS）和稳定同位素分辨代谢组学分析，以评估细胞内代谢物和途径动态的变化。
稳态代谢谱分析显示，参与一碳代谢的代谢物如甘氨酸存在一致的MYC依赖性改变。13C葡萄糖示踪进一步显示，MYC敲低后葡萄糖衍生的丝氨酸和甘氨酸（从头合成）减少，这与该途径的限速酶磷酸甘油酸脱氢酶（PHGDH）的较低表达和活性相一致。此外，与低表达的MBGRP3细胞相比，过表达MYC的细胞对PHGDH的药物抑制更敏感。使用体内荷瘤基因工程小鼠模型和异种移植小鼠模型，PHGDH的药物抑制可提高生存率，这表明从头丝氨酸/甘氨酸合成途径是维持肿瘤进展的促生存机制。至关重要的是，在原发性人类髓母细胞瘤中，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对丝氨酸/甘氨酸途径的依赖性，这为这个预后不良的疾病组提供了一种新的治疗策略。
