Targeting the EWSR1-FLI1 Oncogene-Induced Protein Kinase PKC-β Abolishes Ewing Sarcoma Growth

Surdez, Didier; Benetkiewicz, Magdalena; Perrin, Virginie; Han, Zhi-Yan; Pierron, Gaëlle; Ballet, Steven; Lamoureux, François; Rédini, Françoise; Decouvelaere, Anne‐Valérie; Daudigeos-Dubus, Estelle; Geoerger, Birgit; Pinieux, Gonzague de; Delattre, Olivier; Tirode, Franck

doi:10.1158/0008-5472.can-12-0371

Cited by 60 publications

(43 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1A), which was recently described to be overexpressed in ESFT. PRKCB has been demonstrated to be a direct target of EWS/FLI1, and inhibition of the protein reduces ESFT growth in vitro and in vivo (36). Phosphotyrosine-based rank ordering revealed the most differentially regulated phosphopeptide corresponded to an increase in phosphorylation of STAT3 at tyrosine 705 ( Fig.…”

Section: Ct 818mentioning

confidence: 98%

Phosphoproteomic Profiling Reveals IL6-Mediated Paracrine Signaling within the Ewing Sarcoma Family of Tumors

Anderson

Titz

Akiyama

et al. 2014

Molecular Cancer Research

View full text Add to dashboard Cite

Members of the Ewing sarcoma family of tumors (ESFT) contain tumor-associated translocations that give rise to oncogenic transcription factors, most commonly EWS/FLI1. EWS/FLI1 plays a dominant role in tumor progression by modulating the expression of hundreds of target genes. Here, the impact of EWS/FLI1 inhibition, by RNAi-mediated knockdown, on cellular signaling was investigated using mass spectrometry-based phosphoproteomics to quantify global changes in phosphorylation. This unbiased approach identified hundreds of unique phosphopeptides enriched in processes such as regulation of cell cycle and cytoskeleton organization. In particular, phosphotyrosine profiling revealed a large upregulation of STAT3 phosphorylation upon EWS/FLI1 knockdown. However, single-cell analysis demonstrated that this was not a cell-autonomous effect of EWS/FLI1 deficiency, but rather a signaling effect occurring in cells in which knockdown does not occur. Conditioned media from knockdown cells were sufficient to induce STAT3 phosphorylation in control cells, verifying the presence of a soluble factor that can activate STAT3. Cytokine analysis and ligand/receptor inhibition experiments determined that this activation occurred, in part, through an IL6-dependent mechanism. Taken together, the data support a model in which EWS/FLI1 deficiency results in the secretion of soluble factors, such as IL6, which activate STAT signaling in bystander cells that maintain EWS/FLI1 expression. Furthermore, these soluble factors were shown to protect against apoptosis.

show abstract

Section: Ct 818mentioning

confidence: 98%

Phosphoproteomic Profiling Reveals IL6-Mediated Paracrine Signaling within the Ewing Sarcoma Family of Tumors

Anderson

Titz

Akiyama

et al. 2014

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…Notable was strong (8.1-fold relative mean) mRNA induction of protein kinase C beta (PRKCB) through fusion with USP7, a highly expressed deubiquitinase, in colorectal carcinoma (COAD). PRKCB is a protein kinase linked to tumor growth and survival (32) that is druggable by the small-molecule inhibitor enzastaurin (33). Although fusions involving PRKCB were recently detected in fibrous histiocytoma (34), they have not been described in COAD.…”

Section: Delly Meerkatmentioning

confidence: 99%

Global analysis of somatic structural genomic alterations and their impact on gene expression in diverse human cancers

Alaei-Mahabadi

Bhadury

Karlsson

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Tumor genomes are mosaics of somatic structural variants (SVs) that may contribute to the activation of oncogenes or inactivation of tumor suppressors, for example, by altering gene copy number amplitude. However, there are multiple other ways in which SVs can modulate transcription, but the general impact of such events on tumor transcriptional output has not been systematically determined. Here we use whole-genome sequencing data to map SVs across 600 tumors and 18 cancers, and investigate the relationship between SVs, copy number alterations (CNAs), and mRNA expression. We find that 34% of CNA breakpoints can be clarified structurally and that most amplifications are due to tandem duplications. We observe frequent swapping of strong and weak promoters in the context of gene fusions, and find that this has a measurable global impact on mRNA levels. Interestingly, several long noncoding RNAs were strongly activated by this mechanism. Additionally, SVs were confirmed in telomere reverse transcriptase (TERT) upstream regions in several cancers, associated with elevatedTERTmRNA levels. We also highlight high-confidence gene fusions supported by both genomic and transcriptomic evidence, including a previously undescribed paired box 8 (PAX8)–nuclear factor, erythroid 2 like 2 (NFE2L2) fusion in thyroid carcinoma. In summary, we combine SV, CNA, and expression data to provide insights into the structural basis of CNAs as well as the impact of SVs on gene expression in tumors.

show abstract

“…The analysis revealed that 336 genes were upregulated in both murine and human Ewing's sarcomas, including known EWS-FLI1 targets such as Dkk2, Prkcb1, enhancer of zeste homolog 2 (Ezh2), Id2, Nkx2.2, Nr0b1, and Ptpn13 (26)(27)(28)(29)(30)(31)(32). Furthermore, 6,014 genes, including EWS-FLI1 targets such as Aurka, Gstm4, Tert, Tnc, and Upp1, were upregulated in murine Ewing's sarcoma ( Figure 4C, Supplemental Excel File 3, and refs.…”

Section: Figurementioning

confidence: 99%

Ewing’s sarcoma precursors are highly enriched in embryonic osteochondrogenic progenitors

Tanaka¹,

Yamazaki²,

Kanno³

et al. 2014

J. Clin. Invest.

111

View full text Add to dashboard Cite

Ewing's sarcoma is a highly malignant bone tumor found in children and adolescents, and the origin of this malignancy is not well understood. Here, we introduced a Ewing's sarcoma-associated genetic fusion of the genes encoding the RNA-binding protein EWS and the transcription factor ETS (EWS-ETS) into a fraction of cells enriched for osteochondrogenic progenitors derived from the embryonic superficial zone (eSZ) of long bones collected from late gestational murine embryos. EWS-ETS fusions efficiently induced Ewing's sarcoma-like small round cell sarcoma formation by these cells. Analysis of the eSZ revealed a fraction of a precursor cells that express growth/differentiation factor 5 (Gdf5), the transcription factor Erg, and parathyroid hormone-like hormone (Pthlh), and selection of the Pthlh-positive fraction alone further enhanced EWS-ETSdependent tumor induction. Genes downstream of the EWS-ETS fusion protein were quite transcriptionally active in eSZ cells, especially in regions in which the chromatin structure of the ETS-responsive locus was open. Inhibition of β-catenin, poly (ADP-ribose) polymerase 1 (PARP1), or enhancer of zeste homolog 2 (EZH2) suppressed cell growth in a murine model of Ewing's sarcoma, suggesting the utility of the current system as a preclinical model. These results indicate that eSZ cells are highly enriched in precursors to Ewing's sarcoma and provide clues to the histogenesis of Ewing's sarcoma in bone.

show abstract

Targeting the EWSR1-FLI1 Oncogene-Induced Protein Kinase PKC-β Abolishes Ewing Sarcoma Growth

Cited by 60 publications

References 45 publications

Phosphoproteomic Profiling Reveals IL6-Mediated Paracrine Signaling within the Ewing Sarcoma Family of Tumors

Phosphoproteomic Profiling Reveals IL6-Mediated Paracrine Signaling within the Ewing Sarcoma Family of Tumors

Global analysis of somatic structural genomic alterations and their impact on gene expression in diverse human cancers

Ewing’s sarcoma precursors are highly enriched in embryonic osteochondrogenic progenitors

Contact Info

Product

Resources

About