ERBB4 confers metastatic capacity in Ewing sarcoma
Abstract Metastatic spread is the single‐most powerful predictor of poor outcome in Ewing sarcoma (ES). Therefore targeting pathways that drive metastasis has tremendous potential to reduce the burden of disease in ES. We previously showed that activation of the ERBB4 tyrosine kinase suppresses anoi...
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| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2013-05-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.1002/emmm.201202343 |
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| author | Ariadna Mendoza‐Naranjo Amal El‐Naggar Daniel H. Wai Priti Mistry Nikola Lazic Fernanda Rocha Rojas Ayala Isabela Werneck da Cunha Pablo Rodriguez‐Viciana Hongwei Cheng Jose H. Tavares Guerreiro Fregnani Patrick Reynolds Robert J. Arceci Andrew Nicholson Timothy J. Triche Fernando A. Soares Adrienne M. Flanagan Yuzhuo Z. Wang Sandra J. Strauss Poul H. Sorensen |
| author_facet | Ariadna Mendoza‐Naranjo Amal El‐Naggar Daniel H. Wai Priti Mistry Nikola Lazic Fernanda Rocha Rojas Ayala Isabela Werneck da Cunha Pablo Rodriguez‐Viciana Hongwei Cheng Jose H. Tavares Guerreiro Fregnani Patrick Reynolds Robert J. Arceci Andrew Nicholson Timothy J. Triche Fernando A. Soares Adrienne M. Flanagan Yuzhuo Z. Wang Sandra J. Strauss Poul H. Sorensen |
| author_sort | Ariadna Mendoza‐Naranjo |
| collection | DOAJ |
| description | Abstract Metastatic spread is the single‐most powerful predictor of poor outcome in Ewing sarcoma (ES). Therefore targeting pathways that drive metastasis has tremendous potential to reduce the burden of disease in ES. We previously showed that activation of the ERBB4 tyrosine kinase suppresses anoikis, or detachment‐induced cell death, and induces chemoresistance in ES cell lines in vitro. We now show that ERBB4 is transcriptionally overexpressed in ES cell lines derived from chemoresistant or metastatic ES tumours. ERBB4 activates the PI3K‐Akt cascade and focal adhesion kinase (FAK), and both pathways contribute to ERBB4‐mediated activation of the Rac1 GTPase in vitro and in vivo. ERBB4 augments tumour invasion and metastasis in vivo, and these effects are blocked by ERBB4 knockdown. ERBB4 expression correlates significantly with reduced disease‐free survival, and increased expression is observed in metastatic compared to primary patient‐matched ES biopsies. Our findings identify a novel ERBB4‐PI3K‐Akt‐FAK‐Rac1 pathway associated with aggressive disease in ES. These results predict that therapeutic targeting of ERBB4, alone or in combination with cytotoxic agents, may suppress the metastatic phenotype in ES. |
| format | Article |
| id | doaj-art-c83cff4a9f6f4ec1bb1b67c8bb286c36 |
| institution | OA Journals |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2013-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-c83cff4a9f6f4ec1bb1b67c8bb286c362025-08-20T02:18:33ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842013-05-01571087110210.1002/emmm.201202343ERBB4 confers metastatic capacity in Ewing sarcomaAriadna Mendoza‐Naranjo0Amal El‐Naggar1Daniel H. Wai2Priti Mistry3Nikola Lazic4Fernanda Rocha Rojas Ayala5Isabela Werneck da Cunha6Pablo Rodriguez‐Viciana7Hongwei Cheng8Jose H. Tavares Guerreiro Fregnani9Patrick Reynolds10Robert J. Arceci11Andrew Nicholson12Timothy J. Triche13Fernando A. Soares14Adrienne M. Flanagan15Yuzhuo Z. Wang16Sandra J. Strauss17Poul H. Sorensen18UCL Cancer Institute, University College LondonDepartment of Molecular Oncology, BC Cancer Research CentreChildren's Hospital Los Angeles, Los AngelesUCL Cancer Institute, University College LondonDepartment of Molecular Oncology, BC Cancer Research CentreDepartment of Pathology, Hospital A.C CamargoDepartment of Pathology, Hospital A.C CamargoUCL Cancer Institute, University College LondonDepartment of Molecular Oncology, BC Cancer Research CentreDepartment of Pathology, Hospital A.C CamargoTexas Tech University, School of MedicineKimmel Comprehensive Cancer Centre at Johns Hopkins, BaltimoreDepartment of Histopathology, Royal Brompton HospitalChildren's Hospital Los Angeles, Los AngelesDepartment of Pathology, Hospital A.C CamargoUCL Cancer Institute, University College LondonDepartment of Molecular Oncology, BC Cancer Research CentreUCL Cancer Institute, University College LondonUCL Cancer Institute, University College LondonAbstract Metastatic spread is the single‐most powerful predictor of poor outcome in Ewing sarcoma (ES). Therefore targeting pathways that drive metastasis has tremendous potential to reduce the burden of disease in ES. We previously showed that activation of the ERBB4 tyrosine kinase suppresses anoikis, or detachment‐induced cell death, and induces chemoresistance in ES cell lines in vitro. We now show that ERBB4 is transcriptionally overexpressed in ES cell lines derived from chemoresistant or metastatic ES tumours. ERBB4 activates the PI3K‐Akt cascade and focal adhesion kinase (FAK), and both pathways contribute to ERBB4‐mediated activation of the Rac1 GTPase in vitro and in vivo. ERBB4 augments tumour invasion and metastasis in vivo, and these effects are blocked by ERBB4 knockdown. ERBB4 expression correlates significantly with reduced disease‐free survival, and increased expression is observed in metastatic compared to primary patient‐matched ES biopsies. Our findings identify a novel ERBB4‐PI3K‐Akt‐FAK‐Rac1 pathway associated with aggressive disease in ES. These results predict that therapeutic targeting of ERBB4, alone or in combination with cytotoxic agents, may suppress the metastatic phenotype in ES.https://doi.org/10.1002/emmm.201202343ERBB4Ewing sarcomaFAKmetastasisRac1 |
| spellingShingle | Ariadna Mendoza‐Naranjo Amal El‐Naggar Daniel H. Wai Priti Mistry Nikola Lazic Fernanda Rocha Rojas Ayala Isabela Werneck da Cunha Pablo Rodriguez‐Viciana Hongwei Cheng Jose H. Tavares Guerreiro Fregnani Patrick Reynolds Robert J. Arceci Andrew Nicholson Timothy J. Triche Fernando A. Soares Adrienne M. Flanagan Yuzhuo Z. Wang Sandra J. Strauss Poul H. Sorensen ERBB4 confers metastatic capacity in Ewing sarcoma EMBO Molecular Medicine ERBB4 Ewing sarcoma FAK metastasis Rac1 |
| title | ERBB4 confers metastatic capacity in Ewing sarcoma |
| title_full | ERBB4 confers metastatic capacity in Ewing sarcoma |
| title_fullStr | ERBB4 confers metastatic capacity in Ewing sarcoma |
| title_full_unstemmed | ERBB4 confers metastatic capacity in Ewing sarcoma |
| title_short | ERBB4 confers metastatic capacity in Ewing sarcoma |
| title_sort | erbb4 confers metastatic capacity in ewing sarcoma |
| topic | ERBB4 Ewing sarcoma FAK metastasis Rac1 |
| url | https://doi.org/10.1002/emmm.201202343 |
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