SS18-SSX–Dependent YAP/TAZ Signaling in Synovial Sarcoma

Isfort, Ilka; Cyra, Magdalene; Elges, Sandra; Kailayangiri, Sareetha; Altvater, Bianca; Steinestel, Konrad; Grünewald, Inga; Huss, Sebastian; Eßeling, Eva; Mikesch, Jan‐Henrik; Hafner, Susanne; Simmet, Thomas; Woźniak, Agnieszka; Schöffski, Patrick; Larsson, Olle; Wardelmann, Eva; Trautmann, Marcel; Hartmann, Wolfgang

doi:10.1158/1078-0432.ccr-17-3553

Cited by 39 publications

(31 citation statements)

References 50 publications

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“…Verteporfin effectively reduced U-2OS cell viability, with an IC50 value of 1.44 ± 0.46 μM. As demonstrated in other tumors, including synovial sarcoma [25], verteporfin led to a dose- and time-dependent reduction in the expression (Fig. 4a) and activity (Fig.…”

Section: Resultssupporting

confidence: 58%

ROCK2 deprivation leads to the inhibition of tumor growth and metastatic potential in osteosarcoma cells through the modulation of YAP activity

Zucchini

Manara

Cristalli

et al. 2019

J Exp Clin Cancer Res

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BackgroundThe treatment of metastatic osteosarcoma (OS) remains a challenge for oncologists, and novel therapeutic strategies are urgently needed. An understanding of the pathways that regulate OS dissemination is required for the design of novel treatment approaches. We recently identified Rho-associated coiled-coil containing protein kinase 2 (ROCK2) as a crucial driver of OS cell migration. In this study, we explored the impact of ROCK2 disruption on the metastatic capabilities of OS cells and analyzed its functional relationship with Yes-associated protein-1 (YAP), the main transcriptional mediator of mechanotransduction signaling.MethodsThe effects of ROCK2 depletion on metastasis were studied in NOD Scid gamma (NSG) mice injected with U-2OS cells in which ROCK2 expression had been stably silenced. Functional studies were performed in vitro in human U-2OS cells and in three novel cell lines derived from patient-derived xenografts (PDXs) by using standard methods to evaluate malignancy parameters and signaling transduction. The nuclear immunostaining of YAP and the evaluation of its downstream targets Cysteine Rich Angiogenic Inducer 6, Connective Tissue Growth Factor and Cyclin D1 by quantitative PCR were performed to analyze YAP activity. The effect of the expression and activity of ROCK2 and YAP on tumor progression was analyzed in 175 OS primary tumors.ResultsThe silencing of ROCK2 markedly reduced tumor growth and completely abolished the metastatic ability of U-2OS cells. The depletion of ROCK2, either by pharmacological inhibition or silencing, induced a dose- and time-dependent reduction in the nuclear expression and transcriptional activity of YAP. The nuclear expression of YAP was observed in 80/175 (46%) tumor samples and was significantly correlated with worse patient prognosis and a higher likelihood of metastasis and death. The use of verteporfin, a molecule that specifically inhibits the TEAD–YAP association, remarkably impaired the growth and migration of OS cells in vitro. Moreover to inhibiting YAP activity, our findings indicate that verteporfin also affects the ROCK2 protein and its functions.ConclusionsWe describe the functional connection between ROCK2 and YAP in the regulation of OS cell migration and metastasis formation. These data provide support for the use of verteporfin as a possible therapeutic option to prevent OS cell dissemination.

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Section: Resultssupporting

confidence: 58%

ROCK2 deprivation leads to the inhibition of tumor growth and metastatic potential in osteosarcoma cells through the modulation of YAP activity

Zucchini

Manara

Cristalli

et al. 2019

J Exp Clin Cancer Res

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“…Other pediatric sarcomas such as rhabdomyosarcoma, osteosarcoma, and neuroblastoma have been reported to express YAP1 and TAZ, with an impact on patient prognosis and conferring resistance to current therapies [37][38][39][40][41]. Moreover, recent studies have revealed that YAP1/TAZ are key signaling mediators of the oncogenic fusion genes in synovial sarcoma, myxoid liposarcoma, and alveolar rhabdomyosarcoma [42][43][44]. This positive functional cooperation in translocated sarcomas contrasts with the antagonism between YAP1/TAZ and EWS-FLI1 that we have observed in EwS.…”

Section: Discussionmentioning

confidence: 99%

Hippo pathway effectors YAP1/TAZ induce an EWS–FLI1‐opposing gene signature and associate with disease progression in Ewing sarcoma

Rodríguez‐Núñez

Romero‐Pérez²,

Amaral

et al. 2020

The Journal of Pathology

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YAP1 and TAZ (WWTR1) oncoproteins are the final transducers of the Hippo tumor suppressor pathway. Deregulation of the pathway leads to YAP1/TAZ activation fostering tumorigenesis in multiple malignant tumor types, including sarcoma. However, oncogenic mutations within the core components of the Hippo pathway are uncommon. Ewing sarcoma (EwS), a pediatric cancer with low mutation rate, is characterized by a canonical fusion involving the gene EWSR1 and FLI1 as the most common partner. The fusion protein is a potent driver of oncogenesis, but secondary alterations are scarce, and little is known about other biological factors that determine the risk of relapse or progression. We have observed YAP1/TAZ expression and transcriptional activity in EwS cell lines. Analyses of 55 primary human EwS samples revealed that high YAP1/TAZ expression was associated with progression of the disease and predicted poorer outcome. We did not observe recurrent SNV or copy number gains/losses in Hippo pathway‐related loci. However, differential CpG methylation of the RASSF1 locus (a regulator of the Hippo pathway) was observed in EwS cell lines compared with mesenchymal stem cells, the putative cell of origin of EwS. Hypermethylation of RASSF1 correlated with the transcriptional silencing of the tumor suppressor isoform RASFF1A, and transcriptional activation of the pro‐tumorigenic isoform RASSF1C, which promotes YAP1/TAZ activation. Knockdown of YAP1/TAZ decreased proliferation and invasion abilities of EwS cells and revealed that YAP1/TAZ transcription activity is inversely correlated with the EWS–FLI1 transcriptional signature. This transcriptional antagonism could be explained partly by EWS–FLI1‐mediated transcriptional repression of TAZ. Thus, YAP1/TAZ may override the transcriptional program induced by the fusion protein, contributing to the phenotypic plasticity determined by dynamic fluctuation of the fusion protein, a recently proposed model for disease dissemination in EwS. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…In alveolar rhabdomyosarcoma, the chimeric PAX3-FOXO1 oncoprotein was found to promote tumorigenesis by inhibition of MST1, and dysregulation of YAP1 8 . We previously described an oncogenic mechanism of aberrant YAP1/Hippo signaling activation mechanistically based on the FUS-DDIT3 33 and SS18-SSX 34 oncoproteins in MLS and SySa which is to some extent reminiscent of the situation in alveolar rhabdomyosarcoma in which the pathognomonic PAX3-FOXO1 protein promotes tumorigenesis by Hippo pathway suppression 8 .…”

Section: Discussionmentioning

confidence: 99%

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

Isfort

Elges

Cyra

et al. 2019

Sci Rep

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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.

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SS18-SSX–Dependent YAP/TAZ Signaling in Synovial Sarcoma

Cited by 39 publications

References 50 publications

ROCK2 deprivation leads to the inhibition of tumor growth and metastatic potential in osteosarcoma cells through the modulation of YAP activity

ROCK2 deprivation leads to the inhibition of tumor growth and metastatic potential in osteosarcoma cells through the modulation of YAP activity

Hippo pathway effectors YAP1/TAZ induce an EWS–FLI1‐opposing gene signature and associate with disease progression in Ewing sarcoma

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

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