MB-15 * ACTIVATED Wnt SIGNALING TARGETS Sox2+ TREATMENT-REFRACTORY Shh-DEPENDENT MEDULLOBLASTOMA STEM CELLS
Bibliographic record
Abstract
Medulloblastoma (MB) represents the most frequent malignant pediatric brain tumor. Since MBs characterized by activated sonic hedgehog (Shh) signaling continue to pose significant challenges due to treatment resistance, we aimed to prospectively identify, characterize, and target treatment-refractory Shh-dependent MB stem cells. Using gene expression and clinical outcome data from 325 primary human MBs, we identified Sox2high patients to exclusively represent treatment-refractory Shh MB. In order to prospectively characterize Sox2+ MB stem cells, we took advantage of the CRISPR-Cas9-nickase system to knock-in a P2A-mAG sequence into the Sox2 locus. By using our Sox2 reporter we show enchanced and reduced Sox2 expression in response to small molecule Shh agonists and inhibitors, respectively. Subsequent co-enrichment of Gli1/2 and H3K4me3 at the Sox2 promoter confirmed Sox2 as a downstream target in MB. In order to establish the clinical significance of this mechanism, we treated xenografts with a modified COG ACNS0332 radio/chemo-therapy protocol and prospectively tracked the in vivo evolution of Sox2+ cells. Molecular and functional analyses following treatment yielded an increase in Sox2 expression and self-renewal potential. Given the excellent clinical outcome in Wnt-driven MB patients, we aimed to convert treatment-resistant Sox2high MB into an ostensibly benign tumor using small molecule Wnt agonists. Wnt treatment resulted in a xenograft survival advantage and complete eradication of Sox2+ MB cells. Our work demonstrates mechanistic insight into the regulation of Sox2 by the Shh pathway and the clinical importance of this interaction by identifying Sox2 as a marker of treatment-resistant Shh MB stem cells. Our treatment model has enabled us to prospectively track the evolution of Sox2+ cells in vivo and thereby target these cells upon relapse. We have futher provided evidence for a novel therapeutic approach in converting aggressive MBs into a clinically-treatable tumor, which may improve the overall survival of children with treatment-refractory Shh-dependent 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) | 0.001 | 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".