The Transcriptional Coactivator TAZ Is a Potent Mediator of Alveolar Rhabdomyosarcoma Tumorigenesis

Deel, Michael D.; Slemmons, Katherine K.; Hinson, Ashley R.; Genadry, Katia C.; Burgess, Breanne A.; Crose, Lisa E.S.; Kuprasertkul, Nina; Oristian, Kristianne M.; Bentley, Rex C.; Linardic, Corinne M.

doi:10.1158/1078-0432.ccr-17-1207

Cited by 17 publications

(19 citation statements)

References 61 publications

(136 reference statements)

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“…For instance, Linardic and co-workers identified a novel NOTCH-YAP1-SOX2 circuit critical for maintaining stem cell plasticity in ERMS ( 210 ). The same group found expression of TAZ in ARMS, in which it supports stemness and promotes drug resistance ( 211 ).…”

Section: Isolation and Characterization Of Cscs In Stsmentioning

confidence: 99%

Soft Tissue Sarcoma Cancer Stem Cells: An Overview

et al. 2018

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Soft tissue sarcomas (STSs) are an uncommon group of solid tumors that can arise throughout the human lifespan. Despite their commonality as non-bony cancers that develop from mesenchymal cell precursors, they are heterogeneous in their genetic profiles, histology, and clinical features. This has made it difficult to identify a single target or therapy specific to STSs. And while there is no one cell of origin ascribed to all STSs, the cancer stem cell (CSC) principle—that a subpopulation of tumor cells possesses stem cell-like properties underlying tumor initiation, therapeutic resistance, disease recurrence, and metastasis—predicts that ultimately it should be possible to identify a feature common to all STSs that could function as a therapeutic Achilles' heel. Here we review the published evidence for CSCs in each of the most common STSs, then focus on the methods used to study CSCs, the developmental signaling pathways usurped by CSCs, and the epigenetic alterations critical for CSC identity that may be useful for further study of STS biology. We conclude with discussion of some challenges to the field and future directions.

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Section: Isolation and Characterization Of Cscs In Stsmentioning

confidence: 99%

Soft Tissue Sarcoma Cancer Stem Cells: An Overview

et al. 2018

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“…This is complemented by numerous in vivo studies that show a role for YAP or TAZ in tumor formation and growth. Many of these studies used xenograft model systems with cancer cells that are either overexpressing wild type or LATS-insensitive YAP or TAZ [ 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 ], or in which YAP or TAZ have been knocked down [ 79 , 84 , 85 , 90 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 ]. There are also several studies done in transgenic mice with tissue-specific expression of either wild type or LATS-insensitive YAP or TAZ that show increased tumor formation and enhanced growth [ 19 , 84 , 102 , 103 , 104 , 105 ].…”

Section: Yap/taz-tead Drives Cancer Formation Tumor Growth and Mmentioning

confidence: 99%

“…There are also several studies done in transgenic mice with tissue-specific expression of either wild type or LATS-insensitive YAP or TAZ that show increased tumor formation and enhanced growth [ 19 , 84 , 102 , 103 , 104 , 105 ]. Expression of Hippo pathway-insensitive Yki or YAP also causes tumor formation in Drosophila [ 99 , 106 ]. Knockout of MST1 or MST2 [ 16 , 107 , 108 ], LATS1 or LATS2 [ 109 ], SAV1 [ 108 ], MOB [ 110 , 111 ], or NF2 [ 104 , 112 ] also enhances tumor formation and growth and, in many cases, this was YAP/TAZ-dependent.…”

Section: Yap/taz-tead Drives Cancer Formation Tumor Growth and Mmentioning

confidence: 99%

YAP/TAZ Activation as a Target for Treating Metastatic Cancer

Warren

Xiao

2018

Cancers

135

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Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ) have both emerged as important drivers of cancer progression and metastasis. YAP and TAZ are often upregulated or nuclear localized in aggressive human cancers. There is abundant experimental evidence demonstrating that YAP or TAZ activation promotes cancer formation, tumor progression, and metastasis. In this review we summarize the evidence linking YAP/TAZ activation to metastasis, and discuss the roles of YAP and TAZ during each step of the metastatic cascade. Collectively, this evidence strongly suggests that inappropriate YAP or TAZ activity plays a causal role in cancer, and that targeting aberrant YAP/TAZ activation is a promising strategy for the treatment of metastatic disease. To this end, we also discuss several potential strategies for inhibiting YAP/TAZ activation in cancer and the challenges each strategy poses.

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“…et al [38] observed that YAP1 expression can be detected in 47% of samples (in a series of 32 cases) without association with survival, whereas in another study with only 5 cases, 60% and 80% showed YAP1 and TAZ expression respectively [39]. Other pediatric sarcomas such us rhabdomyosarcoma, osteosarcoma or neuroblastoma have been reported to express YAP1 and TAZ, with an impact in patient prognosis and conferring resistance to current therapies [40][41][42][43][44]. Another fact that supports the relevance of YAP1/TAZ and other Hippo signaling effectors in sarcomas is their involvement in recurrent fusion genes in certain histological types, such as epithelioid hemangioendothelioma (WWTR1-CAMTA1,…”

Section: Discussionmentioning

confidence: 99%

Hippo pathway effectors YAP1/TAZ induce a EWS-FLI1-opposing gene signature and associate with disease progression in Ewing Sarcoma

Rodríguez‐Núñez

Romero‐Pérez

Amaral

et al. 2019

Preprint

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YAP1 and TAZ (WWTR1) oncoproteins are the final transducers of 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 EWSR1 gene, 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 RASSF1 locus -a regulator of 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 protumorigenic isoform RASSF1C promoting 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 partly explained 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.interplay between TAZ/YAP1 function with the fusion protein, which fits into a recent model concept for metastatic spreading in EwS based on fluctuations of the expression of the fusion protein [16]. MATERIALS AND METHODS Tumor samplesIn this study we analyzed 88 formalin-fixed paraffin-embedded (FFPE) samples from 68 Ewing sarcoma patients (55 samples corresponding to primary tumor). We also analyzed a subset of 21 frozen samples from the same series. Clinical diagnosis of all the samples was performed according to the World Health Organization (WHO) classification [17], performing fluorescence in situ hybridization (FISH) to assess the presence of EwS translocation in tissue sections, which validates the immunohistochemical diagnosis. The only selection criteria were the availability of pathological data and tissue for tissue microarray (TMA) construction. Medical records were retrospectively reviewed and clinicopathologic information for 55 patients with primary tumor material were retrieved for further analyses (summarized in Table 1). Tissue samples were obtained from the HU...

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The Transcriptional Coactivator TAZ Is a Potent Mediator of Alveolar Rhabdomyosarcoma Tumorigenesis

Cited by 17 publications

References 61 publications

Soft Tissue Sarcoma Cancer Stem Cells: An Overview

Soft Tissue Sarcoma Cancer Stem Cells: An Overview

YAP/TAZ Activation as a Target for Treating Metastatic Cancer

Hippo pathway effectors YAP1/TAZ induce a EWS-FLI1-opposing gene signature and associate with disease progression in Ewing Sarcoma

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