EphA2 Expression in Bone Sarcomas: Bioinformatic Analyses and Preclinical Characterization in Patient-Derived Models of Osteosarcoma, Ewing’s Sarcoma and Chondrosarcoma

Bone sarcomas are a group of heterogeneous malignant mesenchymal tumors. Complete surgical resection is still the cornerstone of treatment, but, in the advanced/unresectable setting, their management remains challenging and not significantly improved by target- and immuno-therapies. We focused on th...

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Autores principales:	Giorgia Giordano, Alessandra Merlini, Giulio Ferrero, Giulia Mesiano, Erika Fiorino, Silvia Brusco, Maria Laura Centomo, Valeria Leuci, Lorenzo D’Ambrosio, Massimo Aglietta, Dario Sangiolo, Giovanni Grignani, Ymera Pignochino
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	target therapies bioinformatics EphA2 osteosarcoma Ewing’s sarcoma chondrosarcoma Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/779f34e736fa4de89f800e07e0ab3ebf
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spelling	oai:doaj.org-article:779f34e736fa4de89f800e07e0ab3ebf2021-11-25T17:08:38ZEphA2 Expression in Bone Sarcomas: Bioinformatic Analyses and Preclinical Characterization in Patient-Derived Models of Osteosarcoma, Ewing’s Sarcoma and Chondrosarcoma10.3390/cells101128932073-4409https://doaj.org/article/779f34e736fa4de89f800e07e0ab3ebf2021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2893https://doaj.org/toc/2073-4409Bone sarcomas are a group of heterogeneous malignant mesenchymal tumors. Complete surgical resection is still the cornerstone of treatment, but, in the advanced/unresectable setting, their management remains challenging and not significantly improved by target- and immuno-therapies. We focused on the tyrosine kinase Eph type-A receptor-2 (EphA2), a key oncoprotein implicated in self-renewal, angiogenesis, and metastasis, in several solid tumors and thus representing a novel potential therapeutic target. Aiming at better characterizing its expression throughout the main bone sarcoma histotypes, we investigated EPHA2 expression in the Cancer Cell Lines Encyclopedia and in public datasets with clinical annotations. looking for correlations with molecular, histopathological and patients’ features and clinical outcomes in a total of 232 osteosarcomas, 197 Ewing’s sarcomas, and 102 chondrosarcomas. We observed EPHA2 expression in bone sarcoma cell lines. We demonstrated higher EPHA2 expression in tumor tissues when compared to normal counterparts. A significant correlation was found between EPHA2 expression and Huvos grade (osteosarcoma) and with worse overall survival (dedifferentiated chondrosarcoma). Next, we characterized EPHA2 expression and activation in bone sarcoma primary tissues and in patient-derived xenografts generated in our laboratory to verify their reliability as in vivo models of osteosarcoma, Ewing’s sarcoma and chondrosarcoma. Furthermore, for the first time, we demonstrated EPHA2 expression in chondrosarcoma, suggesting its potential key role in this histotype. Indeed, we observed a significant dose-dependent antitumor effect of the EphA2-inhibitor ALW-II-41-27 in patient-derived in vitro models. In conclusion, EphA2 targeting represents a promising novel therapeutic strategy against bone sarcomas.Giorgia GiordanoAlessandra MerliniGiulio FerreroGiulia MesianoErika FiorinoSilvia BruscoMaria Laura CentomoValeria LeuciLorenzo D’AmbrosioMassimo AgliettaDario SangioloGiovanni GrignaniYmera PignochinoMDPI AGarticletarget therapiesbioinformaticsEphA2osteosarcomaEwing’s sarcomachondrosarcomaBiology (General)QH301-705.5ENCells, Vol 10, Iss 2893, p 2893 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	target therapies bioinformatics EphA2 osteosarcoma Ewing’s sarcoma chondrosarcoma Biology (General) QH301-705.5
spellingShingle	target therapies bioinformatics EphA2 osteosarcoma Ewing’s sarcoma chondrosarcoma Biology (General) QH301-705.5 Giorgia Giordano Alessandra Merlini Giulio Ferrero Giulia Mesiano Erika Fiorino Silvia Brusco Maria Laura Centomo Valeria Leuci Lorenzo D’Ambrosio Massimo Aglietta Dario Sangiolo Giovanni Grignani Ymera Pignochino EphA2 Expression in Bone Sarcomas: Bioinformatic Analyses and Preclinical Characterization in Patient-Derived Models of Osteosarcoma, Ewing’s Sarcoma and Chondrosarcoma
description	Bone sarcomas are a group of heterogeneous malignant mesenchymal tumors. Complete surgical resection is still the cornerstone of treatment, but, in the advanced/unresectable setting, their management remains challenging and not significantly improved by target- and immuno-therapies. We focused on the tyrosine kinase Eph type-A receptor-2 (EphA2), a key oncoprotein implicated in self-renewal, angiogenesis, and metastasis, in several solid tumors and thus representing a novel potential therapeutic target. Aiming at better characterizing its expression throughout the main bone sarcoma histotypes, we investigated EPHA2 expression in the Cancer Cell Lines Encyclopedia and in public datasets with clinical annotations. looking for correlations with molecular, histopathological and patients’ features and clinical outcomes in a total of 232 osteosarcomas, 197 Ewing’s sarcomas, and 102 chondrosarcomas. We observed EPHA2 expression in bone sarcoma cell lines. We demonstrated higher EPHA2 expression in tumor tissues when compared to normal counterparts. A significant correlation was found between EPHA2 expression and Huvos grade (osteosarcoma) and with worse overall survival (dedifferentiated chondrosarcoma). Next, we characterized EPHA2 expression and activation in bone sarcoma primary tissues and in patient-derived xenografts generated in our laboratory to verify their reliability as in vivo models of osteosarcoma, Ewing’s sarcoma and chondrosarcoma. Furthermore, for the first time, we demonstrated EPHA2 expression in chondrosarcoma, suggesting its potential key role in this histotype. Indeed, we observed a significant dose-dependent antitumor effect of the EphA2-inhibitor ALW-II-41-27 in patient-derived in vitro models. In conclusion, EphA2 targeting represents a promising novel therapeutic strategy against bone sarcomas.
format	article
author	Giorgia Giordano Alessandra Merlini Giulio Ferrero Giulia Mesiano Erika Fiorino Silvia Brusco Maria Laura Centomo Valeria Leuci Lorenzo D’Ambrosio Massimo Aglietta Dario Sangiolo Giovanni Grignani Ymera Pignochino
author_facet	Giorgia Giordano Alessandra Merlini Giulio Ferrero Giulia Mesiano Erika Fiorino Silvia Brusco Maria Laura Centomo Valeria Leuci Lorenzo D’Ambrosio Massimo Aglietta Dario Sangiolo Giovanni Grignani Ymera Pignochino
author_sort	Giorgia Giordano
title	EphA2 Expression in Bone Sarcomas: Bioinformatic Analyses and Preclinical Characterization in Patient-Derived Models of Osteosarcoma, Ewing’s Sarcoma and Chondrosarcoma
title_short	EphA2 Expression in Bone Sarcomas: Bioinformatic Analyses and Preclinical Characterization in Patient-Derived Models of Osteosarcoma, Ewing’s Sarcoma and Chondrosarcoma
title_full	EphA2 Expression in Bone Sarcomas: Bioinformatic Analyses and Preclinical Characterization in Patient-Derived Models of Osteosarcoma, Ewing’s Sarcoma and Chondrosarcoma
title_fullStr	EphA2 Expression in Bone Sarcomas: Bioinformatic Analyses and Preclinical Characterization in Patient-Derived Models of Osteosarcoma, Ewing’s Sarcoma and Chondrosarcoma
title_full_unstemmed	EphA2 Expression in Bone Sarcomas: Bioinformatic Analyses and Preclinical Characterization in Patient-Derived Models of Osteosarcoma, Ewing’s Sarcoma and Chondrosarcoma
title_sort	epha2 expression in bone sarcomas: bioinformatic analyses and preclinical characterization in patient-derived models of osteosarcoma, ewing’s sarcoma and chondrosarcoma
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/779f34e736fa4de89f800e07e0ab3ebf
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EphA2 Expression in Bone Sarcomas: Bioinformatic Analyses and Preclinical Characterization in Patient-Derived Models of Osteosarcoma, Ewing’s Sarcoma and Chondrosarcoma

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