Abstract 3451: Interactions between N-myc and Sox9 promote medulloblastoma and determine cell fate decisions in cerebellar neural stem cells
Bibliographic record
Abstract
Abstract The proto-oncogene MYCN (N-myc in mice) regulates normal brain development, and is often misexpressed in childhood brain tumors, including medulloblastoma. While most medulloblastoma arise independently of Sonic hedgehog (Shh), about ∼25% of are Shh-dependent and have a more favorable prognosis. We recently induced Shh-independent classic and large cell anaplastic medulloblastoma by driving MYCN from the glial Glutamate Transporter 1 promoter in a tet-regulated transgenic mouse model (Swartling et al, 2010). To characterize cell of origin, we used BrdU labeling in premalignant transgenic mice, demonstrating increased proliferation in cerebellar Bergmann glial cells. Bergmann glia showed high levels of glial marker GFAP as well as the transcription factor Sox9. Whereas neural stem cells (NSCs) from normal perinatal cerebellum contained a high proportion of Sox9-positive cells, primary cultures of tumor spheres showed low levels of Sox9, suggesting that MYCN suppresses Sox9 during medulloblastoma progression. To clarify mechanism, we transduced wild-type (WT) or mutationally-stabilized N-myc-T58A into GFAP-positive NSCs from perinatal murine cerebellum. Transplantation of N-myc-WT NSCs was insufficient for tumor formation. N-myc-T58A cerebellar NSCs generated both Shh-dependent and Shh-independent medulloblastoma, as a function of prenatal or postnatal cerebellar age, respectively. Expression of Sox9 correlated directly with Sonic Hedgehog (Shh) dependence in both murine and human medulloblastoma samples. In addition, forced expression of Sox9 induced Shh-dependence and self-renewal in the Shh-negative mouse medulloblastoma spheres. Our data suggest 1). A glial cell of origin for MYCN-driven medulloblastoma, and 2). Sox9 as a critical target for MYCN during medulloblastoma initiation, with activation of Sox9 leading to Shh-dependence, and inhibition of Sox9 leading to Shh-independent medulloblastoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3451. doi:10.1158/1538-7445.AM2011-3451
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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) | 0.003 | 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".