MB-36 * WIP1 AUGMENTS SONIC HEDGEHOG (SHH) SIGNALING AND IS A TARGET IN SHH MEDULLOBLASTOMAS
Bibliographic record
Abstract
Sonic Hedgehog (SHH) signaling is active in 30% of childhood medulloblastomas. Dysregulation of p53 signaling is especially prognostic for poor survival in SHH medulloblastoma. But, p53 is mutated in <10% of medulloblastomas. Genomic analyses have demonstrated high-level amplification of PPM1D (WIP1) in p53 wild-type SHH medulloblastomas. WIP1 functions as an oncogene, in part by inactivating p53. We hypothesized that, in the absence of p53 mutation, WIP1 overexpression augments SHH-driven medulloblastoma tumorigenesis and is an important target in the treatment of SHH-active medulloblastomas. WIP1 overexpression in murine granule neuron precursor (GNP) cells enhanced expression of Shh target genes, increased the percentage of cells in S phase, and increased cell viability in response to Shh stimulation. Although WIP1 is known to primarily act through p53 pathways, we found that the interaction between WIP1 and Shh was partially p53-independent. To further understand WIP1 mechanisms in vivo, we developed a mouse in which WIP1 is expressed in the developing brain under control of the Neurod2 promoter (ND2:WIP1). The external granule layer in early post-natal ND2:WIP1 mice exhibited increased proliferation and expression of Shh downstream targets. When ND2:WIP1 transgenic mice were crossed with SmoA1/SmoA1 medulloblastoma-prone mice, medulloblastoma incidence increased and double transgenic SmoA1/SmoA1; ND2:WIP1+ mice demonstrated reduced survival. Conversely, Wip1 knock out significantly suppressed medulloblastoma formation in SmoA1/SmoA1 as well as Tamoxifen-treated Math1-creER; Ptc1 fl/fl mice. Treatment with a lentivirus that knocks down Wip1 or with the WIP1 inhibitor CCT007093 inhibits the effects of Shh stimulation and potentiates the effects of the SHH pathway-inhibiting drugs SANT-1, cyclopamine, or the clinically-relevant LDE225 on the growth of either SmoA1/SmoA1 or Math1-creER + ; Ptc1 fl/fl medulloblastoma cells in vitro. This suggests an important cross-talk between SHH and WIP1 that accelerates tumorigenesis. Our findings also suggest an important role for WIP1 inhibition in the treatment of SHH-active medulloblastomas.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".