Related Experiment Video
Updated: May 11, 2026
A Syngeneic Orthotopic Osteosarcoma Sprague Dawley Rat Model with Amputation to Control Metastasis Rate
Published on: May 3, 2021
ERBB4 confers metastatic capacity in Ewing sarcoma
Ariadna Mendoza-Naranjo1, Amal El-Naggar, Daniel H Wai
1UCL Cancer Institute, University College London, London, UK. a.mendoza@ucl.ac.uk
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.
Insights
Targeting ERBB4 in Ewing sarcoma (ES) may reduce metastasis. Overexpressed ERBB4 activates pathways promoting invasion and chemoresistance, correlating with poor survival in ES patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Metastatic spread is a key predictor of poor outcomes in Ewing sarcoma (ES).
- Targeting metastasis pathways offers potential to reduce ES disease burden.
- ERBB4 tyrosine kinase activation was previously shown to suppress anoikis and induce chemoresistance in ES cells.
Purpose of the Study:
- To investigate the role of ERBB4 in ES metastasis and chemoresistance.
- To identify the downstream pathways activated by ERBB4 in ES.
- To correlate ERBB4 expression with patient survival and metastatic status.
Main Methods:
- Analysis of ERBB4 expression in ES cell lines and patient biopsies.
- Investigating ERBB4-mediated activation of PI3K-Akt, FAK, and Rac1 pathways.
- Assessing the impact of ERBB4 knockdown on tumor invasion and metastasis in vivo.
- Correlating ERBB4 expression with disease-free survival in ES patients.
Main Results:
- ERBB4 is transcriptionally overexpressed in chemoresistant and metastatic ES tumors.
- ERBB4 activates the PI3K-Akt, FAK, and Rac1 pathways, promoting invasion and metastasis.
- ERBB4 knockdown blocks ERBB4-mediated tumor invasion and metastasis.
- Increased ERBB4 expression correlates with reduced disease-free survival and metastatic ES.
Conclusions:
- A novel ERBB4-PI3K-Akt-FAK-Rac1 pathway is associated with aggressive disease in ES.
- Therapeutic targeting of ERBB4 may suppress the metastatic phenotype in ES.
- Combination therapy with ERBB4 inhibitors and cytotoxic agents could be beneficial.
Related Concept Videos
02:38Mitogens and the Cell Cycle
02:30Metastasis
Epithelial-to-Mesenchymal Transition
The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...
01:22Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...