Abstract B40: EWS-FLI1 orchestrates Ewing sarcoma plasticity through a post-translational modification cascade regulating FOXM1 stability
Bibliographic record
Abstract
Abstract Oscillations between proliferative and migratory/invasive cell states are at the core of the metastatic process. Transition between these states involves reversible shifts in transcriptional programs that orchestrate cytoskeletal remodeling. Ewing sarcoma pathogenesis depends on EWS-FLI1, an aberrant ETS transcription factor that drives cellular transformation and proliferation of presumably mesenchymal progenitor cells. Recently, it has been reported that transient modulation of EWS-FLI1 expression results in an epithelial-to-mesenchymal transition-like phenotype of Ewing sarcoma cells and in increased metastasis (Chaturvedi et al., 2014; Franzetti et al., 2016). It has been proposed that EWS-FLI1 low cells exist in small amounts in primary Ewing sarcoma tumors and thus provide a potential source for tumor dissemination, leading to adverse prognosis. In our studies, we investigate the mechanistic basis of EWS-FLI1 dose-dependent Ewing sarcoma plasticity and recently reported on the activation of an MRTFB/TEAD transcriptional module promoting cytoskeletal reprograming in response to low EWS-FLI1 levels (Katschnig et al., 2016). Here, we show that the proliferative state depends on the activity of nuclear beta-catenin complexed to FOXM1. We find that EWS-FLI1 not only drives FOXM1 expression on the RNA level, but also sustains nuclear FOXM1 stability by a mechanism involving FOXM1 protein demethylation by lysine-specific demethylase 1 (LSD1/KDM1A). Experimental evidence suggests that EWS-FLI1 regulates LSD1 protein stability in Ewing sarcoma cells by directly activating a ubiquitin-specific protease. Modulation of EWS-FLI1 led to loss of expression of the deubiquitinting enzyme (DUB), and consequently to rapid depletion of LSD1 and FOXM1 proteins and subcellular redistribution of beta-catenin to the cytoplasm. Genetic (siRNA) and pharmacologic inhibition of the DUB or LSD1 recapitulated the destabilizing effect on FOXM1 in EWS-FLI1-high Ewing sarcoma cells, blocking tumor cell proliferation. In addition, they led to complete loss of beta-catenin expression by a mechanism that is currently under investigation. Therefore, our study identifies targetable enzymatic activities downstream of EWS-FLI1 that are required to sustain Ewing sarcoma proliferation. Citation Format: Jozef Ban, Dave Aryee, Lisa Bierbaumer, Heinrich Kovar. EWS-FLI1 orchestrates Ewing sarcoma plasticity through a post-translational modification cascade regulating FOXM1 stability [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B40.
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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) | 0.006 | 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".