Involvement of the TGF-β Signaling Pathway in the Development of YAP-Driven Osteosarcoma Lung Metastasis
Sarah Morice1, Geoffroy Danieau1, Robel Tesfaye1
1Université de Nantes, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche (INSERM UMR) 1238, Nantes, France.
Background:
The poor survival rate of patients with osteosarcoma (OS), specifically with metastases at diagnosis, undergoes the urgency to develop new therapeutic strategies. Although we recently demonstrated the key role of YAP/TEAD signaling in the growth of OS primary tumor, the molecular mechanisms by which YAP regulates metastases development remain poorly understood.
Methods:
The molecular mechanisms by which YAP regulates metastases development were studied using an overexpression of mutated forms of YAP able or not able to interact with TEAD. Molecular signatures were identified using RNA-sequencing analysis and gene set enrichment. Interactions between YAP and Smad3 were studied using proximity ligation assay (PLA), immunoprecipitation, and promoter/specific gene assays. The involvement of the TGF-β pathway in the ability of YAP to stimulate metastatic development in vivo was studied using an inhibitor of the TGF-β cascade in a preclinical model of OS and in vitro on the ability of OS cells to migrate and invade.
Results:
Our work shows that a high YAP expression is associated with the presence of lung metastases which predicts a poor prognosis. Molecular analysis indicates that TGF-β signaling is involved in YAP-driven osteosarcoma cell pro-migratory phenotype, epithelial mesenchymal transition, cell migration, and in vivo lung metastasis development. Regardless of its ability to bind to TEAD, YAP interacts with Smad3 and stimulates the transcriptional activity of TGF-β/Smad3, thereby enhancing the ability of TGF-β to stimulate lung metastasis development.
Conclusions:
We demonstrated the crucial involvement of the TGF-β/Smad3 signaling pathway in YAP-driven lung metastasis development in OS.
Insights
High YAP expression drives osteosarcoma (OS) lung metastasis by interacting with TGF-β/Smad3 signaling, independent of TEAD binding. This finding highlights a new therapeutic target for improving OS patient survival.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Osteosarcoma (OS) has a poor survival rate, especially with metastases.
- New therapeutic strategies are urgently needed.
- The role of YAP/TEAD signaling in primary OS growth is known, but its role in metastasis is unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms by which YAP regulates OS metastasis.
- To investigate the interaction between YAP and TGF-β/Smad3 signaling in OS metastasis.
Main Methods:
- Overexpression of mutated YAP forms to assess TEAD interaction.
- RNA-sequencing and gene set enrichment for molecular signatures.
- Proximity ligation assay, immunoprecipitation, and gene assays to study YAP-Smad3 interactions.
- Inhibition of TGF-β pathway in preclinical OS models and in vitro cell migration/invasion assays.
Main Results:
- High YAP expression correlates with lung metastases and poor prognosis in OS patients.
- TGF-β signaling mediates YAP-driven OS cell migration, epithelial-mesenchymal transition, and lung metastasis.
- YAP interacts with Smad3, independently of TEAD binding, to enhance TGF-β/Smad3 transcriptional activity and promote lung metastasis.
Conclusions:
- The TGF-β/Smad3 signaling pathway is crucial for YAP-driven lung metastasis in osteosarcoma.
- Targeting the YAP-TGF-β/Smad3 axis may offer a novel therapeutic strategy for metastatic OS.
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