title: 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 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.
authors.affiliation: UCL Cancer Institute, University College London, London, UK. a.mendoza@ucl.ac.uk
authors.forename: Ariadna
authors.initials: A
authors.lastname: Mendoza-Naranjo
authors.forename: Amal
authors.initials: A
authors.lastname: El-Naggar
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Wai
authors.forename: Priti
authors.initials: P
authors.lastname: Mistry
authors.forename: Nikola
authors.initials: N
authors.lastname: Lazic
authors.forename: Fernanda Rocha Rojas
authors.initials: FR
authors.lastname: Ayala
authors.forename: Isabela Werneck
authors.initials: IW
authors.lastname: da Cunha
authors.forename: Pablo
authors.initials: P
authors.lastname: Rodriguez-Viciana
authors.forename: Hongwei
authors.initials: H
authors.lastname: Cheng
authors.forename: Jose H
authors.initials: JH
authors.lastname: Tavares Guerreiro Fregnani
authors.forename: Patrick
authors.initials: P
authors.lastname: Reynolds
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Arceci
authors.forename: Andrew
authors.initials: A
authors.lastname: Nicholson
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Triche
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Soares
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Flanagan
authors.forename: Yuzhuo Z
authors.initials: YZ
authors.lastname: Wang
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Strauss
authors.forename: Poul H
authors.initials: PH
authors.lastname: Sorensen
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D066247:Receptor, ErbB-4; D012512:Sarcoma, Ewing / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D015854:Up-Regulation; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D019869:Phosphatidylinositol 3-Kinases; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein
keywords: ERBB4; Ewing sarcoma; FAK; Rac1; metastasis