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

Oncogenesis (2021-01-10)
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Nuclei Isolation Kit: Nuclei EZ Prep, sufficient for 25 nuclei preparations (~1-10×107 cells/preparation)
Sigma-Aldrich
Duolink® In Situ Orange Starter Kit Mouse/Rabbit
Sigma-Aldrich
Verteporfin, ≥94% (HPLC)
Sigma-Aldrich
3-(Biphenyl-4-yl)-5-(4-tert-butylphenyl)-4-phenyl-4H-1,2,4-triazole, 97%