SG-04 * THE eEF2 KINASE, A MEDIATOR OF MEDULLOBLASTOMA ADAPTATION TO METABOLIC STRESS, SUPPORTS FATTY ACID OXIDATION
Bibliographic record
Abstract
During tumour progression, brain tumour cells are exposed to nutrient deprivation due to defective tumour vasculature. The ability of brain tumour cells to adapt to reduced nutrient availability favours selection for aggressive clones. The molecular pathways supporting such metabolic adaptation are still poorly defined. We previously reported that the translation elongation factor 2 kinase (eEF2K), which controls mRNA translation at the step of elongation, is an evolutionarily conserved mediator of the response to nutrient deprivation. Gene expression analysis show that eEF2K expression is upregulated in the most aggressive subgroup of medulloblastoma (MB), namely group 3, and that high eEF2K expression is strongly associated with poor survival in both MB. In addition, genetic targeting of eEF2K significantly increases sensitivity of MB cells to nutrient deprivation, supporting a role for eEF2K in facilitating adaptation of MB to nutrient stress. To decipher the basis for eEF2K protective functions under nutrient deprivation, we performed gene expression analysis of eEF2K proficient versus deficient cells under nutrient-deprived conditions. Gene set enrichment analysis (GSEA) highlighted fatty acid oxidation (FAO) as one of the biological pathways most dramatically deregulated upon eEF2K loss. Remarkably, many genes involved in FAO are downregulated in eEF2K deficient cells under starvation, including genes encoding acyl-coA synthetases and acyl-coA dehydrogenases. Furthermore, cells lacking eEF2K are deficient in metabolizing exogenous palmitate to produce ATP, strongly supporting a role for eEF2K in stimulating FAO activity. Finally, our data show that pharmacological induction of FAO in eEF2K deficient cells using bezafibrate was sufficient to rescue cell death occurring under nutrient depleted conditions. The molecular basis for eEF2K-mediated regulation of the FAO transcriptional program is under investigation. Together, our work supports a critical role for eEF2K in driving FAO activity under nutrient deprivation, which could profoundly impact medulloblastoma adaptation to nutrient stress and therefore emergence of aggressive phenotypes.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".