The YAP/TEAD Axis as a New Therapeutic Target in Osteosarcoma: Effect of Verteporfin and CA3 on Primary Tumor Growth.

Abstract

Simple SummaryThe low survival rate of osteosarcoma (OS) patients underlines the urgency of developing new therapeutic strategies for this disease. In recent years, the important role of Hippo/YAP signaling in cancer has been evaluated, focusing on the possibility of targeting this signaling pathway as an anti-cancer strategy. The aims of this work were (1) to identify a Hippo/YAP signature in OS patients, (2) to define the role of YAP in OS primary tumor growth, (3) to elucidate the role of TEAD in YAP-driven OS tumor growth in vivo, and (4) to evaluate the effects of verteporfin and CA3, two specific YAP-inhibitors, on the OS tumors growth. Our work identifies the YAP/TEAD axis as a promising therapeutic target in OS and demonstrates that verteporfin and CA3, through regulation of OS cells apoptosis, could be a promising therapeutic strategy for inhibiting OS primary tumor growth.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. RNA-seq analysis and Kaplan–Meier assays identified a YAP signature in osteosarcoma patients and a correlation with patients’ outcomes. Molecular and cellular analysis (RNAseq, PLA, immunoprecipitation, promoter/specific gene, proliferation, cell cycle assays) 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 using an orthotopic mice model of osteosarcoma 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. We 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.