ERBB4 confers metastatic capacity in Ewing sarcoma. Issue 7 (16th May 2013)

• Record Type: Journal Article
• Authors: Mendoza‐Naranjo, Ariadna; El‐Naggar, Amal; Wai, Daniel H.; Mistry, Priti; Lazic, Nikola; Ayala, Fernanda Rocha Rojas; da Cunha, Isabela Werneck; Rodriguez‐Viciana, Pablo; Cheng, Hongwei; Tavares Guerreiro Fregnani, Jose H.; Reynolds, Patrick; Arceci, Robert J.; Nicholson, Andrew; Triche, Timothy J.; Soares, Fernando A.; Flanagan, Adrienne M.; Wang, Yuzhuo Z.; Strauss, Sandra J.; Sorensen, Poul H.
• Is Part Of: EMBO molecular medicine. Volume 5:Issue 7(2013:Jul.)
• Page Start: 1087
• Page End: 1102
• Publication Date: 2013-05-16
• Subjects: Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.1002/emmm.201202343
• Languages: English
• ISSNs: 1757-4676

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="emmm201202343-sec-0001" sec-type="section"> <p>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 <italic>anoikis</italic>, or detachment‐induced cell death, and induces chemoresistance in ES cell lines <italic>in vitro</italic>. 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 <italic>in vitro</italic> and <italic>in vivo</italic>. ERBB4 augments tumour invasion and metastasis <italic>in vivo</italic>, and these effects are blocked by <italic>ERBB4</italic> 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.</p> </sec> </abstract>