Cell-to-cell heterogeneity of EWSR1-FLI1 activity determines proliferation/migration choices in Ewing sarcoma cells

Franzetti, G-A; Laud-Duval, Karine; Ent, Wietske van der; Brisac, Anne-Marie; Irondelle, Marie; Aubert, Sébastien; Dirksen, Uta; Bouvier, Corinne; Pinieux, Gonzague de; Snaar‐Jagalska, Ewa; Chavrier, Philippe; Delattre, Olivier

doi:10.1038/onc.2016.498

Cited by 179 publications

(260 citation statements)

References 50 publications

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“…The association of YAP1/TAZ with metastatic spread could arguably be related to the relative levels of the fusion protein, recently reported to promote phenotypic plasticity of EwS cells . In this scenario, YAP1/TAZ may promote a mesenchymal phenotype in EWS–FLI1‐depleted EwS cells together with Wnt/beta‐catenin , since it is well established that the crosstalk between Hippo and Wnt signaling is essential for tumor progression in several types of cancer .…”

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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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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“…Ewing's sarcoma serves as an example proving that only a multidisciplinary approach can result in an adequate diagnosis and treatment, as well as in providing patients with higher possibilities of final recovery. [10][11][12] doi:10.5937/mckg51-14162 COBISS . SR -ID 241717516 UDK.…”

Section: Discussionmentioning

confidence: 99%

Case report of Ewing Sarcoma of the chest wall

Curcic¹,

Lujic²,

Vasovic³

et al. 2017

Medicinski casopis

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“…In addition to murine models, serval groups have also used zebrafish embryonic xenograft models to test novel therapeutics [95,[103][104][105] . Here, cells are injected in the yolk of the embryo, show intra-and extravasation and migration into muscles and fins within 4 days after implantation, making these models interesting for rapid initial screening of a large number of possible therapeutic compounds.…”

Section: In Vivo Modelsmentioning

confidence: 99%

Molecular genetics of Ewing sarcoma, model systems and finding novel (immuno-) therapeutic targets

Ent¹,

Sand²,

Hogendoorn³

2018

JTGG

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Ewing sarcoma (EWS) is a bone-and soft tissue tumour affecting primarily children and young adults. A quarter of patients present with metastases at the time of diagnosis and have a poor outlook in terms of overall survival. Efforts are made across the field to gain deeper insight in the genetics of this enigmatic neoplasm. EWS is characterized by presence of an oncogenic translocation gene, EWSR1-ETS. In addition, there are a limited number of known recurrent DNA copy number variations and mutations. Subsequent of the above, the epigenetic profile of EWS is subject of interest. In this review, we summarize the current available knowledge on the genetics underpinning EWS, explore the current knowledge of its epigenetic profile, discuss in vitro and in vivo model systems, and explore the unravelling knowledge of potential targets for treatment including recent insights into potential immunotherapy.

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Cell-to-cell heterogeneity of EWSR1-FLI1 activity determines proliferation/migration choices in Ewing sarcoma cells

Cited by 179 publications

References 50 publications

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

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

Case report of Ewing Sarcoma of the chest wall

Molecular genetics of Ewing sarcoma, model systems and finding novel (immuno-) therapeutic targets

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