YAP/TAZ inhibition reduces metastatic potential of Ewing sarcoma cells View Full Text


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Article Info

DATE

2021-01-08

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

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. More... »

PAGES

2

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41389-020-00294-8

    DOI

    http://dx.doi.org/10.1038/s41389-020-00294-8

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1134416510

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/33419969


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