Abstract
BackgroundOsteosarcoma is the first primary bone tumor in children and adolescents. Despite progress in the understanding of the biology of these tumors, survival rates have progressed very little in recent decades. In this context, although some studies suggested that disruption of the Hippo signaling pathway is associated with osteosarcoma progression, the molecular mechanisms by which YAP regulates primary tumor growth is not fully clarified. In addition, the validation of YAP as a therapeutic target through the use of inhibitors in a preclinical model must be demonstrated.MethodsThe identification of a YAP signature was carried out by RNAseq analysis from a cohort of patients. Survival rates were assessed by Kaplan-Meier assays. The role of TEAD in the control of osteosarcoma cell proliferation by YAP has been realized by various molecular and cellular biology approaches (RNAseq, PLA, immunoprecipitation, promoter/specific gene, proliferation, cell cycle assays) using overexpression of mutated forms of YAP able or unable to interact with TEAD. The role of TEAD in YAP regulation of primary tumor growth, and the effects of YAP inhibitors in vivo were realized using an orthotopic model of osteosarcoma. ResultsRNA-seq analysis and Kaplan-Meier assays identified a YAP signature in osteosarcoma patients and a correlation with patients outcome. Molecular and cellular analysis using overexpression of mutated forms of YAP able or unable to interact with TEAD, indicate that TEAD is crucial for YAP-driven cell proliferation and in vivo tumor growth. In addition, in vivo experiments show that two YAP/TEAD inhibitors, verteporfin and CA3, reduce primary tumor growth. In this context, in vitro experiments demonstrate that these inhibitors decrease YAP expression, YAP/TEAD transcriptional activity and cell viability mainly by their ability to induce cell apoptosis.ConclusionWe thus demonstrate that the YAP/TEAD signaling axis is a central actor in mediating primary tumor growth of osteosarcoma, and that the use of YAP inhibitors may be a promising therapeutic strategy against osteosarcoma tumor growth.
Tumor cell MT1-MMP is dispensable for osteosarcoma tumor growth, bone degradation and lung metastasis