Abstract PR003: YAP1 is a key regulator of EWS-FLI1-dependent malignant transformation upon IGF1 mediated reprogramming of bone mesenchymal stem cell-like cells
Bibliographic record
Abstract
Abstract Ewing sarcoma (EwS) is driven by the EWS-FLI1 (EF) oncoprotein and is assumed to originate from mesenchymal progenitors during bone development. Attempts to generate a EwS genetic mouse model by targeting EF expression to the mesenchymal lineage so far failed to result in tumorigenesis. Here, we investigated the influence of bone niche-derived factors on EF dependent transformation. We focused on IGF1 which is highly enriched in the bone during puberty when EwS incidence peaks, and which was previously proposed to play an essential role in EwS pathogenesis. We restricted EF expression to mesenchymal stem cells during endochondral bone formation by crossing an EF knock-in mouse with a mouse expressing Prx1-driven Cre recombinase. The resulting EFprx1 progeny died after birth as consequence of severe skeletal malformations resulting from differentiation arrest of early chondrocytes. In vitro, these embryonic EF transgenic chondrocyte-like mesenchymal stem cells (EFprx1 MSCLC) are immortal, but largely failed to form colonies in soft-agar as functional surrogate of full malignant transformation. In contrast, when treated with IGF1 for 4 weeks, a significant increase in soft-agar colony formation was observed, which was dependent on sustained EF expression. Strikingly, cells from these colonies maintained their transformed phenotype in absence of further IGF1 treatment and gave rise to aggressively growing tumors upon xenotransplantation in mice. Analysis of differentially expressed genes from these stably IGF1-reprogrammed, fully transformed EFprx1 MSCLC showed a significant enrichment for the EwS specific EF transcriptional signature with upregulation of Foxm1 and cell cycle-related pathways, and down-regulation of apoptotic gene sets. Cluster analysis of open chromatin regions in EF immortalized versus fully transformed and wildtype cells revealed five distinct chromatin modules. Of these, module 2 comprises genomic regions that open up exclusively in IGF1 reprogrammed EF expressing cells. Among associated genes, Yap1 was most highly induced in IGF1 reprogrammed EFprx1 MSCLC. Consistent with this finding, RNA-seq revealed enrichment of a Yap1 transcriptional signature in IGF1 reprogrammed versus parental EF expressing cells. In addition, chromatin module 4, which comprises regions open in parental and IGF1 reprogrammed EFprx1 MSCLC but not in wildtype MSC, is highly enriched in binding motifs for TEAD transcription factors, the functional effectors of YAP1 signaling. We therefore hypothesize that YAP1 induction by IGF1 reprogramming synergizes with EF in the activation of module 4 genes. Strikingly, modules 2 and 4 comprise hallmark genes of stemness and self-renewal which also characterize human EwS, including Bcl11b, Prkcb, Sox2, Ccnd1, and Klf5, as well as the top EwS dependency gene Igf2bp1. Our data suggest that transient IGF1 exposure in the bone microenvironment during puberty may be required for EF driven EwS tumor initiation, and we identify a central role of YAP1 in the early phases of EwS pathogenesis. Citation Format: Heinrich Kovar, Rahil Noorizadeh, Florian Halbritter, Utkarsh Kapoor, Wolfgang Mikulits, Richard Moriggl, Barbara Sax. YAP1 is a key regulator of EWS-FLI1-dependent malignant transformation upon IGF1 mediated reprogramming of bone mesenchymal stem cell-like cells [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr PR003.
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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".