Mendoza-Naranjo, A;
El-Naggar, A;
Wai, DH;
Mistry, P;
Lazic, N;
Ayala, FR;
da Cunha, IW;
... Sorensen, PH; + view all
(2013)
ERBB4 confers metastatic capacity in Ewing sarcoma.
EMBO Mol Med
, 5
(7)
1019 - 1034.
10.1002/emmm.201202343.
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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.
| Type: | Article |
|---|---|
| Title: | ERBB4 confers metastatic capacity in Ewing sarcoma. |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/emmm.201202343 |
| Publisher version: | http://dx.doi.org/10.1002/emmm.201202343 |
| Language: | English |
| Additional information: | © 2013 EMBO Molecular Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMCID: PMC3721475 |
| Keywords: | ERBB4, Ewing sarcoma, FAK, Rac1, metastasis, Bone Neoplasms, Bone and Bones, Cell Line, Tumor, Cell Movement, Enzyme Activation, Gene Expression Regulation, Neoplastic, Humans, Neoplasm Metastasis, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Receptor, Epidermal Growth Factor, Sarcoma, Ewing, Signal Transduction, Up-Regulation, rac1 GTP-Binding Protein |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Pathology |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1394052 |
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