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

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.