CSIG-10. SHH-MEDULLOBLASTOMA PREFERENTIALLY ARISES FROM GRANULE CELL PRECURSORS IN THE LATERAL CEREBELLUM
Bibliographic record
Abstract
The cerebellar tumor Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Aggressive treatments including surgery, radiotherapy and chemotherapy for these young patients can greatly affect their motor control and cognitive and social behaviors controlled by the cerebellum. Mechanistic studies of MB progression are urgently needed in order to develop less toxic targeted therapies. MB is divided into four subgroups: WNT, SHH, Group 3 and Group 4. SHH-MB comprises 30% of all MBs and the main cell type of origin is granule cell progenitors (GCPs), which comprise a transient amplifying population in the developing cerebellum regulated by SHH signaling. We utilized inducible recombinases to overexpress a constitutively active form of SMO (SmoM2) or delete Ptch1 in few GCPs at Postnatal (P) day 2. Interestingly, we found that 200 SmoM2 mutant cells are sufficient to generate tumors and all tumors develop only in the lateral cerebellum (hemispheres). This finding correlates with MRI studies showing that SHH-MB subgroup patients have tumors preferentially in the hemispheres, whereas the other subgroups are found almost exclusively in the midline (vermis). We hypothesized that SHH-MB arises mainly in the hemispheres because GCPs are intrinsically different in this location. By using a mosaic analysis to test whether susceptibility to hyperactivation of the SHH pathway is regionally regulated, we discovered that Ptch1/SmoM2 mutant GCPs in the hemispheres indeed differentiate less compared to the vermis. Microarray analysis of P8 GCPs and P21 pre-neoplastic lesions revealed subsets of genes that are differentially expressed between the vermis and hemispheres, and between the two stages. We are validating candidate genes that could contribute to tumorigenesis. Our studies should provide new insights into the cellular and genetic mechanisms underlying SHH-MB progression, and to the identification of novel drug targets to aid in development of new therapies for this childhood tumor.
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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 | 0.001 |
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".