The EWSR1/NR4A3 fusion protein of extraskeletal myxoid chondrosarcoma activates the <i>PPARG</i> nuclear receptor gene

Filion, Christine; Motoi, Toru; Olshen, Adam B.; Laé, Marick; Emnett, Ryan J.; Gutmann, David H.; Perry, Arie; Ladanyi, Marc; Labelle, Yves

doi:10.1002/path.2445

Cited by 58 publications

(59 citation statements)

References 53 publications

(62 reference statements)

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“…The 739 probe sets on the U133A chip corresponded to 432 genes with kinase domains, representing 83% of the 518 known protein kinase genes. (Note: this microarray expression analysis was utilized in a previous publication as a comparator data set for a study of myxoid chondrosarcoma (26)).…”

Section: Resultsmentioning

confidence: 99%

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PDGF Receptor Alpha Is an Alternative Mediator of Rapamycin-Induced Akt Activation: Implications for Combination Targeted Therapy of Synovial Sarcoma

Vasudeva

Laé

et al. 2012

Cancer Research

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Akt activation by the IGF-1 receptor (IGF-1R) has been posited to be a mechanism of intrinsic resistance to mTORC1 inhibitors ("rapalogues") for sarcomas. Here we demonstrate that rapamycin-induced phosphorylation of Akt can occur in an IGF-1R-independent manner. Analysis of synovial sarcoma cell lines demonstrated that either the IGF-1R or the PDGF receptor alpha (PDGFRA) could mediate intrinsic resistance to rapamycin. Repressing expression of PDGFRA or inhibiting its kinase activity in synovial sarcoma cells blocked rapamycin-induced phosphorylation of Akt and decreased tumor viability. Expression profiling of clinical tumor samples revealed that PDGFRA was the most highly expressed kinase gene among several sarcoma disease subtypes, suggesting that PDGFRA may be uniquely significant for synovial sarcomas. Tumor biopsy analyses from a synovial sarcoma patient treated with the mTORC1 inhibitor everolimus and PDGFRA inhibitor imatinib mesylate confirmed that this drug combination can impact both mTORC1 and Akt signals in vivo. Together, our findings define mechanistic variations in the intrinsic resistance of synovial sarcomas to rapamycin and suggest therapeutic strategies to address them.

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Section: Resultsmentioning

confidence: 99%

“…Microarray data were normalized with the robust multi-array average (RMA) method. These expression microarray data are previously published (26) and are freely available at: http://cbio.mskcc.org/Public/sarcoma_array_data/.…”

Section: Methodsmentioning

confidence: 99%

PDGF Receptor Alpha Is an Alternative Mediator of Rapamycin-Induced Akt Activation: Implications for Combination Targeted Therapy of Synovial Sarcoma

Vasudeva

Laé

et al. 2012

Cancer Research

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“…Also, a t(9;17)(q22;q11) and a t(9;15) (q22;q21) are found, fusing the NR4A3 gene with RBP56 and TAF15, respectively. Recent data indicate that the EWSR1/NR4A3 fusion protein may activate the PPARG nuclear receptor gene that may not only play a key role in the molecular oncogenesis of EMCS but also represents a potential therapeutic target [100].…”

Section: Cytogenetics and Molecular Geneticsmentioning

confidence: 99%

Soft tissue tumors associated with EWSR1 translocation

2009

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The Ewing sarcoma breakpoint region 1 (EWSR1; also known as EWS) represents one of the most commonly involved genes in sarcoma translocations. In fact, it is involved in a broad variety of mesenchymal lesions which includes Ewing's sarcoma/peripheral neuroectodermal tumor, desmoplastic small round cell tumor,clear cell sarcoma, angiomatoid fibrous histiocytoma, extraskeletal myxoid chondrosarcoma, and a subset of myxoid liposarcoma. The fusion products between EWSR1 and partners usually results in fusion of the N-terminal transcription-activating domain of EWSR1 and the C-terminal DNA-binding domain of the fusion partner, eventually generating novel transcription factors. EWSR1 rearrangement can be visualized by the means of fluorescence in situ hybridization (FISH). As soft tissue sarcomas represent a diagnostically challenging group, FISH analysis is an extremely useful confirmatory diagnostic tool. However, as in most instances a split-apart approach is used, the results of molecular genetics must be evaluated in context with morphology.

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“…To determine whether neural genes are enriched in primary DSRCT, we analyzed the expression profile of 28 primary DSRCT performed previously in comparison with four other tumor types (31). GO analysis of genes that are upregulated (>2-fold) in DSRCT compared with either Ewing sarcoma (ES), alveolar rhabdomyosarcoma (ARMS), or alveolar soft part sarcoma (ASPS) revealed an enrichment of neural pathways (Supplementary Table S2), but not when compared with synovial sarcoma (SS).…”

Section: Neural Genes Are Overexpressed In Primary Dsrctmentioning

confidence: 99%

EWS–WT1 Oncoprotein Activates Neuronal Reprogramming Factor ASCL1 and Promotes Neural Differentiation

et al. 2014

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The oncogenic fusion gene EWS-WT1 is the defining chromosomal translocation in desmoplastic small roundcell tumors (DSRCT), a rare but aggressive soft tissue sarcoma with a high rate of mortality. EWS-WT1 functions as an aberrant transcription factor that drives tumorigenesis, but the mechanistic basis for its pathogenic activity is not well understood. To address this question, we created a transgenic mouse strain that permits physiologic expression of EWS-WT1 under the native murine Ews promoter. EWS-WT1 expression led to a dramatic induction of many neuronal genes in embryonic fibroblasts and primary DSRCT, most notably the neural reprogramming factor ASCL1. Mechanistic analyses demonstrated that EWS-WT1 directly bound the proximal promoter of ASCL1, activating its transcription through multiple WT1-responsive elements. Conversely, EWS-WT1 silencing in DSRCT cells reduced ASCL1 expression and cell viability. Notably, exposure of DSRCT cells to neuronal induction media increased neural gene expression and induced neurite-like projections, both of which were abrogated by silencing EWS-WT1. Taken together, our findings reveal that EWS-WT1 can activate neural gene expression and direct partial neural differentiation via ASCL1, suggesting agents that promote neural differentiation might offer a novel therapeutic approach to treat DSRCT. Cancer Res; 74(16); 4526-35. Ó2014 AACR.

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The EWSR1/NR4A3 fusion protein of extraskeletal myxoid chondrosarcoma activates the PPARG nuclear receptor gene

Cited by 58 publications

References 53 publications

PDGF Receptor Alpha Is an Alternative Mediator of Rapamycin-Induced Akt Activation: Implications for Combination Targeted Therapy of Synovial Sarcoma

PDGF Receptor Alpha Is an Alternative Mediator of Rapamycin-Induced Akt Activation: Implications for Combination Targeted Therapy of Synovial Sarcoma

Soft tissue tumors associated with EWSR1 translocation

EWS–WT1 Oncoprotein Activates Neuronal Reprogramming Factor ASCL1 and Promotes Neural Differentiation

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