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.
Highlights
Ewing sarcoma (ES) is the second most common bone tumour in children and adolescents (Riggi & Stamenkovic, 2007)
ERBB4 is overexpressed in cell lines derived from ES To screen for potential markers of aggressive disease in ES, we compared gene expression profiles (GEPs) in CHLA-10 versus CHLA-9 ES cell lines
Western blotting demonstrated dramatically higher expression of the full-length 180 kDa ERBB4 species in CHLA-10 compared to CHLA-9 cells under conventional monolayer (M) culture conditions, which was further enhanced in non-adherent suspension (S) cultures of the same cell lines (Fig 1B)
Summary
Ewing sarcoma (ES) is the second most common bone tumour in children and adolescents (Riggi & Stamenkovic, 2007). These tumours are characterized by etiologic gene fusions of EWS to different members of the ETS transcription factor family, and the expression of chimeric EWS–ETS fusion proteins such as EWS-. Multi-modality therapy has greatly improved the outcome for ES patients, and those with localized disease at diagnosis have 5-year survival rates approaching 70% (Damron et al, 2007). Patients with metastatic disease have a dismal outcome with 5-year survival rates of only 15–25% (Linabery & Ross, 2008).
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