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 of YAP1/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 of YAP1 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 of YAP1 and TAZ, corresponding to their transcriptionally active pool. Suppression of YAP1/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 of YAP1/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 from YAP1/TAZ-TEAD directed therapeutic approaches within future clinical trials.
Highlights
The Yes associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ) are central effectors of the Hippo signaling pathway, which is essential in regulating tissue homeostasis and organ size[1]
Recent studies demonstrate an essential role of YAP1/TAZ in sarcomagenesis implying that a YAP1/TAZ-directed therapeutic approach could represent a rational strategy in selected entities[5,6,7,8,9,10,27,28,29,30,31]
TAZ-TEAD inhibition. (A) Viability of sarcoma cells was significantly reduced by treatment with increasing concentrations of the YAP1/TAZ-TEAD inhibitor verteporfin (0.125–2 μmol/L; ***P < 0.001; **P < 0.01) in vitro
Summary
The Yes associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ) are central effectors of the Hippo signaling pathway, which is essential in regulating tissue homeostasis and organ size[1]. Activated LATS1/2 in turn phosphorylates YAP1 and TAZ, leading to their cytoplasmic retention through the interaction with a Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. In the inactive state of the Hippo signaling cascade, non-phosphorylated YAP1 and TAZ translocate into the nucleus and interact with transcription factors such as TEA domain transcription factor 1-4 (TEAD 1-4) to induce expression of downstream target genes that promote e.g. cell proliferation and suppression of apoptosis. We analyzed a large cohort of specimens of soft tissue and bone tumors and sarcoma cell lines to delineate the prevalence of YAP1/TAZ expression in order to identify subgroups of tumors which might be dependent on Hippo-YAP1/TAZ signals and might profit from therapeutic YAP1/TAZ inhibition
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