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YAP1 Enhances Mesenchymal-Type Gene Expression in Human Adrenergic-Type Neuroblastoma Cells.
Marius Ludwig1,2, Kerstin Ahrens1, Annika Winkler1
1Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Virchow Klinikum, 13353 Berlin, Germany.
The YAP1 protein drives neuroblastoma cells toward a mesenchymal state, increasing aggressiveness and resistance to chemotherapy. This reprogramming highlights YAP1 as a potential therapeutic target for neuroblastoma treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Neuroblastoma cells exhibit phenotypic plasticity, interconverting between mesenchymal and adrenergic states.
- The mesenchymal state, marked by core genes like YAP1, is associated with poor prognosis.
- Previous studies indicated Hippo-YAP pathway activation during neuroblastoma relapse.
Purpose of the Study:
- To investigate the role of YAP1 in neuroblastoma aggressiveness.
- To explore YAP1's influence on neuroblastoma response to therapy.
- To elucidate the mechanisms underlying YAP1-mediated phenotypic plasticity.
Main Methods:
- Assessed YAP1 expression using RT-qPCR and immunoblotting in neuroblastoma cell lines.
- Utilized RNA sequencing to identify YAP1-dependent gene signatures in SK-N-AS and SH-EP cell models.
- Compared gene expression data from cell models with existing tumor data and analyzed chemotherapy efficacy.
Main Results:
- YAP1 expression varied significantly across neuroblastoma cell lines at both mRNA and protein levels.
- Constitutive YAP1 activation upregulated mesenchymal signature genes and transcription factors.
- YAP1 activation in neuroblastoma cells conferred resistance to standard chemotherapeutics.
Conclusions:
- YAP1 plays a mechanistic role in the adrenergic to mesenchymal transition and therapy resistance in neuroblastoma.
- YAP1-induced mesenchymal reprogramming may offer novel therapeutic strategies for neuroblastoma.
- Targeting YAP1 could overcome treatment resistance and improve outcomes in neuroblastoma.
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