ERBB4 confers metastatic capacity in Ewing sarcoma

EMBO Mol Med. 2013 Jul;5(7):1087-102. doi: 10.1002/emmm.201202343. Epub 2013 May 16.


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.

Keywords: ERBB4; Ewing sarcoma; FAK; Rac1; metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Neoplasms / genetics
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology*
  • Bone and Bones / metabolism
  • Bone and Bones / pathology*
  • Cell Line, Tumor
  • Cell Movement
  • Enzyme Activation
  • ErbB Receptors / genetics*
  • ErbB Receptors / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Neoplasm Metastasis / genetics
  • Neoplasm Metastasis / pathology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, ErbB-4
  • Sarcoma, Ewing / genetics
  • Sarcoma, Ewing / metabolism
  • Sarcoma, Ewing / pathology*
  • Signal Transduction
  • Up-Regulation
  • rac1 GTP-Binding Protein / metabolism


  • Phosphatidylinositol 3-Kinases
  • ERBB4 protein, human
  • ErbB Receptors
  • Receptor, ErbB-4
  • Proto-Oncogene Proteins c-akt
  • rac1 GTP-Binding Protein