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Prevalence of the Hippo Effectors YAP1/TAZ in Tumors of Soft Tissue and Bone

Journal article
Authors I. Isfort
S. Elges
M. Cyra
R. Berthold
M. Renner
G. Mechtersheimer
Pierre Åman
O. Larsson
N. Ratner
S. Hafner
T. Simmet
C. Schliemann
C. Rossig
U. Dirksen
I. Grunewald
E. Wardelmann
S. Huss
W. Hartmann
M. Trautmann
Published in Scientific Reports
Volume 9
ISSN 2045-2322
Publication year 2019
Published at Sahlgrenska Cancer Center
Institute of Biomedicine
Language en
Links dx.doi.org/10.1038/s41598-019-56247...
Keywords growth in-vitro, therapeutic target, pathway, yap, fusion, tead, inhibition, subset, cells, Science & Technology - Other Topics
Subject categories Pathology, Cancer and Oncology

Abstract

Tumors of soft tissue and bone represent a heterogeneous group of neoplasias characterized by a wide variety of genetic aberrations. Albeit knowledge on tumorigenesis in mesenchymal tumors is continuously increasing, specific insights on altered signaling pathways as a basis for molecularly targeted therapeutic strategies are still sparse. The aim of this study was to determine the involvement ofYAP1/TAZ-mediated signals in tumors of soft tissue and bone. Expression levels of YAP1 and TAZ were analyzed by immunohistochemistry in a large cohort of 486 tumor specimens, comprising angiosarcomas (AS), Ewing sarcomas, leiomyosarcomas, malignant peripheral nerve sheath tumors (MPNST), solitary fibrous tumors, synovial sarcomas (SySa), well-differentiated/dedifferentiated/ pleomorphic and myxoid liposarcomas (MLS). Moderate to strong nuclear staining ofYAP1 and TAZ was detected in 53% and 33%, respectively. YAP1 nuclear expression was most prevalent in MPNST, SySa and MLS, whereas nuclear TAZ was predominately detected in AS, MLS and MPNST. In a set of sarcoma cell lines, immunoblotting confirmed nuclear localization ofYAP1 and TAZ, corresponding to their transcriptionally active pool. Suppression ofYAP1/TAZ-TEAD mediated transcriptional activity significantly impaired sarcoma cell viability in vitro and in vivo. Our findings identify nuclear YAP1 and TAZ positivity as a common feature in subsets of sarcomas of soft tissue and bone and provide evidence ofYAP1/TAZ-TEAD signaling as a specific liability to be considered as a new target for therapeutic intervention. Nuclear YAP1/TAZ expression may represent a biomarker suited to identify patients that could benefit fromYAP1/TAZ-TEAD directed therapeutic approaches within future clinical trials.

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