MB-107REST ELEVATION UNRESTRAINS SHH SIGNALING IN MEDULLOBLASTOMA
Bibliographic record
Abstract
Medulloblastoma (MB) is a malignant pediatric brain tumor characterized by poor neuronal differentiation. The RE1 Silencing Transcription Factor (REST), a repressor of neurogenesis, is overexpressed in human MBs. The elevated expression of REST in a subset of patients with desmoplastic MB is associated with poor prognosis. To understand the underlying mechanisms, we generated a novel knock-in mouse expressing human REST transgene in a conditional manner in granule cell progenitors (GCPs), the cells of origin of sonic hedgehog (Shh) driven MB. Mice with constitutive activation of sonic hedgehog signaling and REST elevation (RESTKI/Ptc+/-) in their GCPs developed tumors with a significant decrease in latency and increase in penetrance. We observed that 100% of RESTKI/Ptc+/- animals developed heterogeneously proliferative and undifferentiated tumors with a striking increase in neural stem cell marker expression compared to tumor-bearing Ptc+/- animals. Mechanistic studies revealed direct transcriptional repression of Ptc by REST, which caused a total loss of Ptc expression in Ptc haploinsufficient GCPs. REST elevation in Ptc+/- GCPs also promoted significant Gli-1 dependent upregulation of the brain specific isoforms of Akt, and activation of AKT signaling. Consistent with this, 100% of RESTKI/Ptc+/- animals developed highly vascularized, infiltrative tumors with a propensity for leptomeningeal dissemination. Thus, our studies suggest that REST elevation and constitutive Shh activation cooperatively drive an aggressive disease course by deregulating proliferation and driving the expansion of a highly undifferentiated cell population, with potential to promote rapid tumor growth and tumor dissemination.
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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 | 0.000 |
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".