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Type of publication: Journal Article
Type of document: Full Paper

Year: 2021

Authors: Bierbaumer, L; Katschnig, AM; Radic-Sarikas, B; Kauer, MO; Petro, JA; Högler, S; Gurnhofer, E; Pedot, G; Schäfer, BW; Schwentner, R; Mühlbacher, K; Kromp, F; Aryee, DNT; Kenner, L; Uren, A; Kovar, H

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

Source: Oncogenesis. 2021; 10(1):2



Authors Vetmeduni Vienna:

Högler Sandra
Kenner Lukas

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals


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.


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