Neuro Oncology | 3型髓母细胞瘤中发现可靶向的代谢节点
专业点燃希望约 7 分钟研究人员建立了三个独立的MYC依赖性MBGRP3细胞模型，分别是D425 med、HDMB03和D283med，这些细胞系均过表达MYC。通过在四环素应答启动子控制下，使用含有Tet-on载体和靶向MYC的shRNA（shMYC1和shMYC2）的慢病毒转导，以及非沉默对照（shNS），实现了MYC的可诱导敲低。在所有模型中，Dox诱导的shMYC1在72小时后显著敲低MYC，而shMYC2的效果较温和。与未处理或shNS对照相比，Dox诱导的shMYC1导致细胞增殖减慢，且这种增殖缺陷与MYC敲低程度一致。研究表明，所有模型均持续依赖MYC生长（即“MYC成瘾”），并适用于MYC依赖性生物学研究。72小时的Dox处理被确定为达到最大MYC敲低和开始生长抑制的有效时间点，而shNS对照为区分MYC依赖效应和Dox相关处理效应提供了背景。
利用1H HRMAS分析代谢物变化（图2A、B） 量化特定代谢物和脂质（补充图3和表2） 关注甘氨酸等关键代谢物（图2D、E，补充图2D、E和补充图3）
图2 MYC表达扰动如何改变MBGRP3细胞的代谢物景观，以及通过HRMAS代谢物谱分析鉴定的重要代谢物变化
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排版 | Sheila 校对 | uu
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*本文由深圳市拾玉儿童公益基金会“儿童肿瘤前沿”团队编译或约稿，文中图表均源引自文献原文。本文著作权归文章作者所有，欢迎个人转发分享，未经允许禁止转载，作者拥有所有法定权利，违者必究。如需转载，请留言或联系[email protected]。本文旨在分享儿童肿瘤科研前沿成果，不是治疗方案推荐。如需获得疾病治疗方案指导，请前往正规医院就诊。
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原文摘要（Abstract）
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.
DOI: 10.1093/neuonc/noae179