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<p>Medulloblastoma, the most common malignant pediatric posterior fossa tumor, exhibits metabolic reprogramming and tumor immune microenvironment heterogeneity in non-WNT/non-SHH subgroups, yet the interplay between these features remains poorly defined. Revealing potential molecular features and hidden therapeutic target, we integrated the transcriptomic data of non-WNT/non-SHH medulloblastoma from GEO and EMBL-EBI databases. Through examination of the Grp3/4 transcriptional continuum, we identified PCK2 (a key gene in the TCA cycle with the highest correlation with continuum score). We validated PCK2 as a driver of proliferation, migration, invasion, glycolysis, and M2 macrophage polarization in MYC-amplified MB cells through short hairpin RNA knockdown experiments. Together, our findings establish metabolic-TIME crosstalk as a prognostic determinant and proffer PCK2 as a therapeutic target for aggressive MB subtypes, offering insights into metabolic subtyping and precision therapy strategies to improve clinical outcomes.</p>

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PCK2 as a potential therapeutic target for aggressive MYC-amplified non-WNT/non-SHH medulloblastoma based on tumor continuum

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月21日

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  • Shuaishuai Xue,
  • Zhengming Zhan,
  • Yonghua Cai,
  • Wei Chen,
  • Ruizhe Chen,
  • Yangqi Mao,
  • Cheng Xie,
  • Jun Liu,
  • Ziyi Luo,
  • Siyuan Liu,
  • Xian Zhang,
  • Peng Li,
  • Hao Long,
  • Ye Song

摘要

Medulloblastoma, the most common malignant pediatric posterior fossa tumor, exhibits metabolic reprogramming and tumor immune microenvironment heterogeneity in non-WNT/non-SHH subgroups, yet the interplay between these features remains poorly defined. Revealing potential molecular features and hidden therapeutic target, we integrated the transcriptomic data of non-WNT/non-SHH medulloblastoma from GEO and EMBL-EBI databases. Through examination of the Grp3/4 transcriptional continuum, we identified PCK2 (a key gene in the TCA cycle with the highest correlation with continuum score). We validated PCK2 as a driver of proliferation, migration, invasion, glycolysis, and M2 macrophage polarization in MYC-amplified MB cells through short hairpin RNA knockdown experiments. Together, our findings establish metabolic-TIME crosstalk as a prognostic determinant and proffer PCK2 as a therapeutic target for aggressive MB subtypes, offering insights into metabolic subtyping and precision therapy strategies to improve clinical outcomes.