YAP/TAZ inhibition reduces metastatic potential of Ewing sarcoma cells.

Abstract

Ewing sarcoma (EwS) is a highly metastatic bone cancer characterized by the ETS fusion oncoprotein EWS-FLI1. EwS cells are phenotypically highly plastic and switch between functionally distinct cell states dependent on EWS-FLI1 fluctuations. Whereas EWS-FLI1high cells proliferate, EWS-FLI1low cells are migratory and invasive. Recently, we reported activation of MRTFB and TEAD, effectors of RhoA and Hippo signalling, upon low EWS-FLI1, orchestrating key steps of the EwS migratory gene expression program. TEAD and its co-activators YAP and TAZ are commonly overexpressed in cancer, providing attractive therapeutic targets. We find TAZ levels to increase in the migratory EWS-FLI1low state and to associate with adverse prognosis in EwS patients. We tested the effects of the potent YAP/TAZ/TEAD complex inhibitor verteporfin on EwS cell migration in vitro and on metastasis in vivo. Verteporfin suppressed expression of EWS-FLI1 regulated cytoskeletal genes involved in actin signalling to the extracellular matrix, effectively blocked F-actin and focal-adhesion assembly and inhibited EwS cell migration at submicromolar concentrations. In a mouse EwS xenograft model, verteporfin treatment reduced relapses at the surgical site and delayed lung metastasis. These data suggest that YAP/TAZ pathway inhibition may prevent EwS cell dissemination and metastasis, justifying further preclinical development of YAP/TAZ inhibitors for EwS treatment.

• Authors: Lisa Bierbaumer, Anna M Katschnig, Branka Radic-Sarikas, Maximilian O Kauer, Jeffrey A Petro, Sandra Högler, Elisabeth Gurnhofer, Gloria Pedot, Beat W Schäfer, Raphaela Schwentner, Karin Mühlbacher, Florian Kromp, Dave N T Aryee, Lukas Kenner, Aykut Uren, Heinrich Kovar
• Journal: Oncogenesis (Oncogenesis) Vol. 10 Issue 1 Pg. 2 (Jan 08 2021) ISSN: 2157-9024 [Print] United States
• PMID: 33419969 (Publication Type: Journal Article)