FUS-CHOP Promotes Invasion in Myxoid Liposarcoma through a SRC/FAK/RHO/ROCK-Dependent Pathway

Deregulated SRC/FAK signaling leads to enhanced migration and invasion in many types of tumors. In myxoid and round cell liposarcoma (MRCLS), an adipocytic tumor characterized by the expression of the fusion oncogene FUS-CHOP, SRC have been found as one of the most activated kinases. Here we used a...

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Autores: Tornín, Juan, Hermida-Prado, Francisco, Padda, Ranjit Singh, González, M. Victoria, Álvarez-Fernández, Carlos, Rey, Verónica, Martínez-Cruzado, Lucía, Estupiñán, Óscar, Menéndez, Sofía T., Fernández-Nevado, Lucía, Astudillo, Aurora, Rodrigo, Juan P., Lucien, Fabrice, Kim, Yohan, Leong, Hon S., García-Pedrero, Juana María, Rodríguez, René
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/414332
Acceso en línea:http://hdl.handle.net/10261/414332
https://api.elsevier.com/content/abstract/scopus_id/85035103728
Access Level:acceso abierto
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spelling FUS-CHOP Promotes Invasion in Myxoid Liposarcoma through a SRC/FAK/RHO/ROCK-Dependent PathwayTornín, JuanHermida-Prado, FranciscoPadda, Ranjit SinghGonzález, M. VictoriaÁlvarez-Fernández, CarlosRey, VerónicaMartínez-Cruzado, LucíaEstupiñán, ÓscarMenéndez, Sofía T.Fernández-Nevado, LucíaAstudillo, AuroraRodrigo, Juan P.Lucien, FabriceKim, YohanLeong, Hon S.García-Pedrero, Juana MaríaRodríguez, RenéDeregulated SRC/FAK signaling leads to enhanced migration and invasion in many types of tumors. In myxoid and round cell liposarcoma (MRCLS), an adipocytic tumor characterized by the expression of the fusion oncogene FUS-CHOP, SRC have been found as one of the most activated kinases. Here we used a cell-of-origin model of MRCLS and an MRCLS cell line to thoroughly characterize the mechanisms of cell invasion induced by FUS-CHOP using in vitro (3D spheroid invasion assays) and in vivo (chicken chorioallantoic membrane model) approaches. FUS-CHOP expression activated SRC-FAK signaling and increased the invasive ability of MRCLS cells. In addition, FAK expression was found to significantly correlate with tumor aggressiveness in sarcoma patient samples. The involvement of SRC/FAK activation in FUS-CHOP–mediated invasion was further confirmed using the SRC inhibitor dasatinib, the specific FAK inhibitor PF-573228, and FAK siRNA. Notably, dasatinib and PF573228 could also efficiently block the invasion of cancer stem cell subpopulations. Downstream of SRC/FAK signaling, we found that FUS-CHOP expression increases the levels of the RHO/ROCK downstream effector phospho-MLC2 (T18/S19) and that this activation was prevented by dasatinib or PF573228. Moreover, the ROCK inhibitor RKI-1447 was able to completely abolish invasion in FUS-CHOP–expressing cells. These data uncover the involvement of SRC/FAK/RHO/ROCK signaling axis in FUS-CHOP–mediated invasion, thus providing a rationale for testing inhibitors of this pathway as potential novel antimetastatic agents for MRCLS treatment.This work was supported by the Agencia Estatal de Investigación (AEI) [MINECO/Fondo Europeo de Desarrollo Regional (FEDER) (SAF-2013-42,946-R and SAF-2016-75,286-R to R.R.), ISC III/FEDER (Miguel Servet II Program CPII16/00049 to R.R. and PI13/00259 and PI16/00280 to J.M.G-P) and Consorcio CIBERONC CB16/12/00390 to J.P.R)] and the Plan de Ciencia Tecnología e Innovación del Principado de Asturias (GRUPIN14-003) to J. P. R. H. S. L. is supported by Prostate Cancer Canada Rising Star Grant (RS2016-1011).Peer reviewedElsevierAgencia Estatal de Investigación (España)Ministerio de Economía y Competitividad (España)European CommissionPrincipado de AsturiasProstate Cancer Foundation202620262018info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/414332https://api.elsevier.com/content/abstract/scopus_id/85035103728reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO//SAF2013-42946-Rinfo:eu-repo/grantAgreement/AEI//SAF2016-75286-Rhttps://doi.org/10.1016/j.neo.2017.11.004Noinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4143322026-05-22T06:33:51Z
dc.title.none.fl_str_mv FUS-CHOP Promotes Invasion in Myxoid Liposarcoma through a SRC/FAK/RHO/ROCK-Dependent Pathway
title FUS-CHOP Promotes Invasion in Myxoid Liposarcoma through a SRC/FAK/RHO/ROCK-Dependent Pathway
spellingShingle FUS-CHOP Promotes Invasion in Myxoid Liposarcoma through a SRC/FAK/RHO/ROCK-Dependent Pathway
Tornín, Juan
title_short FUS-CHOP Promotes Invasion in Myxoid Liposarcoma through a SRC/FAK/RHO/ROCK-Dependent Pathway
title_full FUS-CHOP Promotes Invasion in Myxoid Liposarcoma through a SRC/FAK/RHO/ROCK-Dependent Pathway
title_fullStr FUS-CHOP Promotes Invasion in Myxoid Liposarcoma through a SRC/FAK/RHO/ROCK-Dependent Pathway
title_full_unstemmed FUS-CHOP Promotes Invasion in Myxoid Liposarcoma through a SRC/FAK/RHO/ROCK-Dependent Pathway
title_sort FUS-CHOP Promotes Invasion in Myxoid Liposarcoma through a SRC/FAK/RHO/ROCK-Dependent Pathway
dc.creator.none.fl_str_mv Tornín, Juan
Hermida-Prado, Francisco
Padda, Ranjit Singh
González, M. Victoria
Álvarez-Fernández, Carlos
Rey, Verónica
Martínez-Cruzado, Lucía
Estupiñán, Óscar
Menéndez, Sofía T.
Fernández-Nevado, Lucía
Astudillo, Aurora
Rodrigo, Juan P.
Lucien, Fabrice
Kim, Yohan
Leong, Hon S.
García-Pedrero, Juana María
Rodríguez, René
author Tornín, Juan
author_facet Tornín, Juan
Hermida-Prado, Francisco
Padda, Ranjit Singh
González, M. Victoria
Álvarez-Fernández, Carlos
Rey, Verónica
Martínez-Cruzado, Lucía
Estupiñán, Óscar
Menéndez, Sofía T.
Fernández-Nevado, Lucía
Astudillo, Aurora
Rodrigo, Juan P.
Lucien, Fabrice
Kim, Yohan
Leong, Hon S.
García-Pedrero, Juana María
Rodríguez, René
author_role author
author2 Hermida-Prado, Francisco
Padda, Ranjit Singh
González, M. Victoria
Álvarez-Fernández, Carlos
Rey, Verónica
Martínez-Cruzado, Lucía
Estupiñán, Óscar
Menéndez, Sofía T.
Fernández-Nevado, Lucía
Astudillo, Aurora
Rodrigo, Juan P.
Lucien, Fabrice
Kim, Yohan
Leong, Hon S.
García-Pedrero, Juana María
Rodríguez, René
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Agencia Estatal de Investigación (España)
Ministerio de Economía y Competitividad (España)
European Commission
Principado de Asturias
Prostate Cancer Foundation
description Deregulated SRC/FAK signaling leads to enhanced migration and invasion in many types of tumors. In myxoid and round cell liposarcoma (MRCLS), an adipocytic tumor characterized by the expression of the fusion oncogene FUS-CHOP, SRC have been found as one of the most activated kinases. Here we used a cell-of-origin model of MRCLS and an MRCLS cell line to thoroughly characterize the mechanisms of cell invasion induced by FUS-CHOP using in vitro (3D spheroid invasion assays) and in vivo (chicken chorioallantoic membrane model) approaches. FUS-CHOP expression activated SRC-FAK signaling and increased the invasive ability of MRCLS cells. In addition, FAK expression was found to significantly correlate with tumor aggressiveness in sarcoma patient samples. The involvement of SRC/FAK activation in FUS-CHOP–mediated invasion was further confirmed using the SRC inhibitor dasatinib, the specific FAK inhibitor PF-573228, and FAK siRNA. Notably, dasatinib and PF573228 could also efficiently block the invasion of cancer stem cell subpopulations. Downstream of SRC/FAK signaling, we found that FUS-CHOP expression increases the levels of the RHO/ROCK downstream effector phospho-MLC2 (T18/S19) and that this activation was prevented by dasatinib or PF573228. Moreover, the ROCK inhibitor RKI-1447 was able to completely abolish invasion in FUS-CHOP–expressing cells. These data uncover the involvement of SRC/FAK/RHO/ROCK signaling axis in FUS-CHOP–mediated invasion, thus providing a rationale for testing inhibitors of this pathway as potential novel antimetastatic agents for MRCLS treatment.
publishDate 2018
dc.date.none.fl_str_mv 2018
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
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status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/414332
https://api.elsevier.com/content/abstract/scopus_id/85035103728
url http://hdl.handle.net/10261/414332
https://api.elsevier.com/content/abstract/scopus_id/85035103728
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
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info:eu-repo/grantAgreement/MINECO//SAF2013-42946-R
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https://doi.org/10.1016/j.neo.2017.11.004
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dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
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