72P - Role of pyruvate carboxykinase 2 upregulation in group 3 medulloblastoma: Implications for metabolic reprogramming and therapeutic strategies

Background

Group 3 Medulloblastoma (MB) is a subgroup of MB with poor prognosis and high chances of recurrence. The highly aggressive nature of this paediatric brain tumor necessitates targeted therapeutic approaches to improve patient outcomes. Phosphoenolpyruvate carboxykinase plays a crucial role in gluconeogenesis by catalyzing the conversion of oxaloacetate to phosphoenolpyruvate. PCK2 is the mitochondrial counterpart of this enzyme, helping in replenishment of various metabolic intermediates and hence acting as a pivotal protein between pyruvate metabolism, TCA cycle and gluconeogenesis. Recent proteomic studies on Medulloblastoma (MB) suggest extensive metabolic rewiring in Group 3 MB.

Methods

Analysis of publicly available omics data on Medulloblastoma was performed to identify the expression levels of proteins related to key metabolic pathways like Krebs cycle, pyruvate metabolism and glucose metabolism including PCK2. Key proteins belonging to these pathways were analysed in FFPE tissues from MB patients and compared with other subgroups using multiple reaction monitoring. PCK2 was knocked down in Group 3 cell lines using shRNA and evaluated for effects on proliferation and survival using culture based in vitro assays. High resolution label free proteomic analysis was performed to ascertain the effects of PCK2 knockdown.

Results

Data mining and repository data analysis found dysregulation of key proteins and metabolites. Key proteins involved in energy metabolism including PCK2 showed upregulation even at the transcriptomic level. Proteomic analysis on few FFPE samples could validate these findings. shRNA based PCK2 knockdown resulted in lowering the proliferation rates of Group 3 cells and significant changes in their proteomes.

Conclusions

The overexpression of PCK2 is involved in the aggressiveness of Group 3 MB and can be a possible target for this subset of medulloblastoma patients.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

IIT Bombay.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.