MEDU-04. AN OTX2-PAX GENE NETWORK REGULATES GROUP 3 MEDULLOBLASTOMA DIFFERENTIATION AND TUMOR GROWTH
Bibliographic record
Abstract
Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor. Group 3 has the worst prognosis of the MB subgroups and the pathways driving Group 3 pathogenesis are poorly defined. OTX2 is overexpressed/amplified in 80% of Group 3 tumors and maintains the balance between self-renewal and neuronal differentiation. Here, we evaluated the contribution of the OTX2 gene regulatory network in driving Group 3 MB pathogenesis. We mapped changes in active (H3K4me3) and repressive (H3K27me3) histone modifications following OTX2 silencing in Group 3 MB cells. Neuronal differentiation genes encoding transcription factors (TFs) were associated with loss of H3K27me3 modifications suggesting de-repression in TF expression. Members of the PAX gene family of TFs were significantly de-repressed and their role in Group 3 MB progression is unknown. PAX3 and PAX6 expression is significantly lower in Group 3 MB patients and low expression is correlated with significantly reduced patient survival. Interestingly, OTX2 directly binds to PAX3 and PAX6 and restricts their expression in Group 3 MB cells. Over-expressing PAX3 and PAX6 in Group 3 MB cells reduced tumorsphere number, self-renewal and cell cycle properties while increasing neuronal differentiation. In addition, PAX3 expression significantly increased survival and reduced tumor size following intracerebellar transplantation. RNA-sequencing of tumorspheres over-expressing PAX3 and PAX6 revealed a reduction in Group 3 signatures including GABAergic and glutamatergic signalling. Downregulation of genes involved in mTOR signalling was specifically observed in PAX3 over-expressing tumorspheres, which may contribute to the differential survival observed in vivo. Similar changes in gene signatures were also demonstrated following OTX2 silencing in multiple Group 3 MB cell lines. Our results demonstrate that OTX2 controls cell fate decisions in Group 3 MB by regulating PAX gene expression, and that targeting downstream molecular signatures may reveal novel therapeutic targets for these highly aggressive tumors.
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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) | 0.003 | 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".