Abstract A29: Respective role of TEAD and Smad signaling in YAP-mediated osteosarcoma tumor growth and lung metastatic development
Bibliographic record
Abstract
Abstract Osteosarcoma (OS) is the main malignant primary bone tumor in children and adolescents for whom the prognosis remains poor, especially when metastases are present at diagnosis. Because a) gene set enrichment analysis (GSEA) of expression data from a cohort of OS patients reveals a Hippo conserved signature in OS and b) proximity ligation (PLA) and immunoprecipitation (IP) assays have shown an interaction between YAP and TEAD, the main effector of Hippo signaling pathway, in OS cell lines, we investigated its implication in OS development. To elucidate the role of TEAD in YAP-driven OS development, we probed the consequences of YAP activation using overexpression of YAPS127A (constitutively active YAP) and YAPS94A (TEAD-binding deficient YAP protein). Firstly, in vivo and in vitro experiments demonstrate a) the crucial role of TEAD in YAP-driven cell proliferation and in vivo tumor growth and b) a correlation between the expression of TEAD1 and the survival outcomes of OS patients. In this context RNAseq analysis and GSEA identified more than 300 genes related to cell proliferation that are significantly overexpressed in YAPS127A cells compared to control cells and YAPS94A cells. Secondly, we study the effects of YAP/TEAD interactions on the main biologic functions’ links to metastasis dissemination. We show an increase of cell migration using KHOS-S94A and KHOS-S127A, suggesting that YAP/TEAD interaction is not necessary to increase migration in OS. GSEA identifies genes related to epithelial-mesenchymal-transition (EMT), cell migration and TGF-β that are significantly overexpressed in YAPS127A and YAPS94A cells, strongly suggesting that TEAD is not required in YAP-driven expression of genes related to EMT, cell migration, and TGF-β signaling. Thirdly, using PLA and IP, we show an interaction of YAP/SMAD3 in OS cell line independently of YAP/TEAD interaction. In this context, using Tβ²R1 inhibitor, SD-208, we demonstrate the role of TGF-β/smad signaling in YAP-driven cell migration and metastatic process in OS. Finally, we investigated the effect of verteporfin, identified as an inhibitor of the Hippo signaling pathway, on OS progression. In vivo experiments showed that verteporfin reduces primary tumor growth and lung metastases development. In vitro experiments demonstrated that verteporfin decreases cell viability and inhibits the TGF-β/Smad3 cascade and the response of TGF-β key targets involved in the metastasis dissemination process. Together, these results defined the specific role of TEAD and SMAD3 in YAP-driven OS tumor and lung metastatic process. In addition, we demonstrated that YAP could be considered as a therapeutic target in OS. Citation Format: Sarah Morice, Geoffroy Danieau, Mathilde Mullard, Jérôme Amiaud, Régis Brion, Sarah Renault, Robel Tesfaye, Maryne Dupuy, Julie Talbot, Benjamin Ory, Bénédicte Brounais-Le Royer, Isabelle Corre, Anne Brouchet-Gomez, Françoise Rédini, Franck Verrecchia. Respective role of TEAD and Smad signaling in YAP-mediated osteosarcoma tumor growth and lung metastatic development [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 A29.
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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) | 0.004 | 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".