MEDU-14. OTX2 CONTROLS AN AXON GUIDANCE GENE EXPRESSION NETWORK TO REGULATE MEDULLOBLASTOMA SELF-RENEWAL
Bibliographic record
Abstract
Medulloblastoma (MB) is a highly heterogeneous primary malignant pediatric brain cancer that is frequently accompanied by metastatic dissemination and poor long-term prognosis. The most aggressive tumors are refractory to conventional chemotherapy and radiation. Our goal is to identify new signaling pathways that regulate the treatment-resistant MB cellular phenotypes, namely the stem cells. We previously discovered that the OTX2 gene, which is amplified or overexpressed in the majority of aggressive MBs, is a central regulator of stem cell function or self-renewal in these tumors. However, the molecular mechanisms by which OTX2 regulates these functions are still unknown. Here, we employed complementary bioinformatics approaches to characterize the OTX2 regulatory network and identified a novel relationship between OTX2 and genes associated with axon guidance signaling in Group 3 and Group 4 MB stem/progenitor cells. Following OTX2 knockdown, transcripts associated with semaphorin, netrin, ephrin and slit signaling were predominantly upregulated. ChIP-sequencing identified putative OTX2 DNA binding sites and revealed statistically significant associations between OTX2 and these axon guidance pathway genes. Group 3 and 4 MB patient samples were evaluated for correlations between expression of axon guidance pathway genes, OTX2 and survival. Semaphorin signaling was the most overrepresented pathway across all datasets with expression of all pathway genes being upregulated following OTX2 KD. Moreover, SEMA4D expression was identified as a novel prognostic biomarker. Functional validation studies demonstrated that increased levels of semaphorin pathway genes are associated with a decrease in self-renewal underscoring a potential tumor suppressive role in these tumors. Downstream pathways known to mediate the effects of semaphorin signaling including, RHOA and MAPK were also differentially expressed following OTX2 KD. Our results offer critical insights into the molecular drivers of the most aggressive MB tumors and provide an informed framework to pursue novel targeted therapies aimed at differentiating MB tumors cells.
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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) | 0.002 | 0.000 |
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".