PM-01 * NEURAL DERIVATIVES FROM HUMAN EMBRYONIC STEM CELLS: A CELLULAR SYSTEM TO STUDY THE ROLE OF Otx2 IN MEDULLOBLASTOMA PROGRESSION
Bibliographic record
Abstract
Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor and is currently divided into 4 subtypes based on different genomic alterations, gene expression profiles and response to treatment: Wnt, Sonic Hedgehog (Shh), Group 3 and Group 4. This extensive heterogeneity has made it difficult to assess the functional relevance of genes to malignant progression. For example, expression of the transcription factor, Orthodenticle homeobox2 (Otx2) is frequently dysregulated in multiple MB variants; however, its role may be subtype-specific. We recently demonstrated that neural precursors derived from transformed human embryonic stem cells (trans-hENs), but not their normal counterparts (hENs), resemble Groups 3 and 4 MB in vitro and in vivo. These trans-hENs have >12-fold overexpression of Otx2. Here, we tested the utility of this model system as a means of dissecting the role of Otx2 in MB using gain and loss of function studies in hENs and trans-hENs respectively. Parallel experiments with MB cells revealed that Otx2 exerts tumor suppressive effects in hEN and Shh MB cells, likely by regulating self-renewal and decreasing expression of pluripotent genes such as Sox2, Lin28A, Oct4 and Nanog. Concomitant to the negative regulation of hESC genes, we observed a decrease in levels of the active histone mark, H3K4me3 at promoter loci of pluripotent genes as well as an increase in Otx2 recruitment at the Sox2 promoter by chromatin immunoprecipitation assays. This was supported by overexpression of Sox2 in Otx2+ Shh MB and hENs that resulted in significant rescue of self-renewal and cell migration. In contrast, Otx2 is oncogenic and promotes self-renewal of trans-hENs and Groups 3/4 MB independent of pluripotent genes. These results demonstrate a cell context-dependent function of Otx2. Our study underscores the value of hESC derivatives as developmental models of MB and for investigating key biological questions related to embryonal childhood cancers.
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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) | 0.001 | 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 | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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".