STEM-06. OTX2 and LASR drive a pro-tumorigenic splicing program in Group 3 medulloblastoma
Bibliographic record
Abstract
Abstract Medulloblastoma is a disease of aberrant cerebellar development. These embryonic tumors arise from primitive cells in the cerebellar rhombic lip stalled in their developmental processes. The transcription factor OTX2 is critical for maintaining the stem-cell state of Group 3 MB. We recently uncovered a non-canonical role for OTX2 in cell fate decisions, where OTX2 interacts with members of the large assembly of splicing regulators (LASR) complex, orchestrating a novel alternative splicing (AS) program to drive Group 3 MB progression. OTX2 silencing in Group 3 MB cells identified significant splicing alterations with alternatively spliced exons being the most common event. Silencing of OTX2 and LASR proteins HNRNPM and HNRNPC in Group 3 cells uncovered common differentially spliced genes suggesting that these proteins regulate common targets. RNA binding protein motif analysis support these findings, identifying enrichment of motifs for RBFOX2 and HNRNPC near OTX2-regulated spliced exons. To examine the mechanism by which OTX2 regulates AS, we performed enhanced crosslinking and immunoprecipitation (eCLIP) to determine whether OTX2 directly binds RNA or indirectly controls LASR complex binding to regulate AS in Group 3 MB. Our findings suggest that OTX2 affects splicing indirectly through associations with members of the LASR complex, influencing LASR protein binding to mRNA. Splice-blocking morpholinos were utilized to functionally validate oncogenic and inhibitory AS events to investigate their functional relevance in Group 3 MB. Our results show that co-regulated spliced variants contribute to the maintenance of the primitive oncogenic state of Group 3 MB and highlight the post-transcriptional landscape as an important molecular signature of Group 3 MB.Collectively, we have identified a novel role for OTX2 in regulating AS in Group 3 MB. We propose that OTX2 binds to LASR complex proteins, regulating the splicing of neurodevelopmental genes to maintain the pro-tumorigenic stem cell state of Group 3 MB.
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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 | 0.001 |
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".