TY - JOUR
T1 - ERBB4 confers metastatic capacity in Ewing sarcoma
AU - Mendoza-Naranjo, Ariadna
AU - El-Naggar, Amal
AU - Wai, Daniel H.
AU - Mistry, Priti
AU - Lazic, Nikola
AU - Ayala, Fernanda Rocha Rojas
AU - da Cunha, Isabela Werneck
AU - Rodriguez-Viciana, Pablo
AU - Cheng, Hongwei
AU - Tavares Guerreiro Fregnani, Jose H.
AU - Reynolds, Patrick
AU - Arceci, Robert J.
AU - Nicholson, Andrew
AU - Triche, Timothy J.
AU - Soares, Fernando A.
AU - Flanagan, Adrienne M.
AU - Wang, Yuzhuo Z.
AU - Strauss, Sandra J.
AU - Sorensen, Poul H.
PY - 2013/7
Y1 - 2013/7
N2 - 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. The Authors show that ERBB4 is a biological driver of metastasis in the pediatric bone tumour Ewing sarcoma and identify a novel ERBB4-PI3K-Akt-FAK-Rac1 pathway associated with aggressive disease.
AB - 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. The Authors show that ERBB4 is a biological driver of metastasis in the pediatric bone tumour Ewing sarcoma and identify a novel ERBB4-PI3K-Akt-FAK-Rac1 pathway associated with aggressive disease.
KW - ERBB4
KW - Ewing sarcoma
KW - FAK
KW - Metastasis
KW - Rac1
UR - http://www.scopus.com/inward/record.url?scp=84880019478&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84880019478&partnerID=8YFLogxK
U2 - 10.1002/emmm.201202343
DO - 10.1002/emmm.201202343
M3 - Article
C2 - 23681745
AN - SCOPUS:84880019478
SN - 1757-4676
VL - 5
SP - 1019
EP - 1034
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 7
ER -