RT Journal Article
T1 EphA2 receptor is a key player in the metastatic onset of Ewing sarcoma.
A1 Garcia-Monclús, Silvia
A1 López-Alemany, Roser
A1 Almacellas-Rabaiget, Olga
A1 Herrero-Martín, David
A1 Huertas-Martinez, Juan
A1 Lagares-Tena, Laura
A1 Alba-Pavón, Piedad
A1 Hontecillas-Prieto, Lourdes
A1 Mora, Jaume
A1 de Álava, Enrique
A1 Rello-Varona, Santi
A1 Giangrande, Paloma H
A1 Tirado, Oscar M
K1 ADAM19
K1 EphA2
K1 Ewing sarcoma
K1 metastasis
AB Ewing sarcoma (ES) is the second most common bone malignancy affecting children and young adults with poor prognosis due to high metastasis incidence. Our group previously described that EphA2, a tyrosine kinase receptor, promotes angiogenesis in Ewing sarcoma (ES) cells via ligand-dependent signaling. Now we wanted to explore EphA2 ligand-independent activity, controlled upon phosphorylation at S897 (p-EphA2S897 ), as it has been linked to metastasis in several malignancies. By reverse genetic engineering we explored the phenotypic changes after EphA2 removal or reintroduction. Gene expression microarray was used to identify key players in EphA2 signaling. Mice were employed to reproduce metastatic processes from orthotopically implanted engineered cells. We established a correlation between ES cells aggressiveness and p-EphA2S897 . Moreover, stable overexpression of EphA2 in low EphA2 expression ES cells enhanced proliferation and migration, but not a non-phosphorylable mutant (S987A). Consistently, silencing of EphA2 reduced tumorigenicity, migration and invasion in vitro, and lung metastasis incidence in experimental and spontaneous metastasis assays in vivo. A gene expression microarray revealed the implication of EphA2 in cell signaling, cellular movement and survival. ADAM19 knockdown by siRNA technology strongly reproduced the negative effects on cell migration observed after EphA2 silencing. Altogether, our results suggest that p-EphA2S897 correlates with aggressiveness in ES, so blocking its function may be a promising treatment.
YR 2018
FD 2018-04-16
LK http://hdl.handle.net/10668/12280
UL http://hdl.handle.net/10668/12280
LA en
DS RISalud
RD Apr 6, 2025