BIOL-08. RADIATION DRIVES METASTASIS IN MEDULLOBLASTOMA THROUGH AN INFLAMMATORY PROCESS
Bibliographic record
Abstract
Abstract Current treatment for medulloblastoma is comprised of surgery, radiotherapy (RT) and/or chemotherapy. Although the primary tumor is controlled with this approach, recurrent metastatic disease is ubiquitously fatal. However, little is known about the biology of metastatic recurrences in medulloblastoma. In the present study, we observe across 3 non-overlapping cohorts of infant medulloblastoma that patients recur locally without focal RT and metastatically after focal RT. Using 3 independent murine flank xenograft medulloblastoma models, we found that the incidence of leptomeningeal metastasis was significantly increased in mice that received RT compared to sham controls. We have also found a significant increase in viable circulating tumor cells after RT. Our multi-omics (bulk RNA-seq, scRNA-seq and proteo/phosphoproteomics) approach using immunocompetent sporadic medulloblastoma models treated with RT showed activation of the innate inflammatory response through the overexpression of chemokines, cytokines and activation of immune cell types. In situ analysis of protein expression after RT showed a gradual increase in the abundance of macrophages, neutrophils and dendritic cells after RT, suggesting increased permeability and cell trafficking across the blood brain barrier. Applying live intravital microscopy using a low molecular weight vascular dye (150kDa), we observed a striking increase in blood vessel permeability in RT vs sham-treated brain tumors. Our observations support a model where RT drives metastasis through inflammation. To test this, we applied lipopolysaccharide (LPS), an inflammation inducing treatment, to a sporadic murine medulloblastoma model which significantly increased the metastatic burden. We then treated a xenograft model with dexamethasone in combination with RT, which resulted in total abrogation of metastatic dissemination compared to RT alone. Collectively, our findings suggest that while external beam irradiation is an effective and essential treatment for medulloblastoma, it may facilitate metastatic dissemination through an inflammation-induced process. These findings can help inform potential approaches to prevent disseminated relapsed disease.
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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 | 0.001 | 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".