Dual role of integrin Alpha-6 in glioblastoma: supporting stemness in proneural stem-like cells while inducing radioresistance in mesenchymal stem-like cells

Therapeutic resistance after multimodal therapy is the most relevant cause of glioblastoma (GBM) recurrence. Extensive cellular heterogeneity, mainly driven by the presence of GBM stem-like cells (GSCs), strongly correlates with patients' prognosis and limited response to therapies. Definin...

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Autores: Stanzani, Elisabetta, Pedrosa, Leire, Bourmeau, Guillaume, Anezo, Oceane, Noguera-Castells, Aleix, Esteve-Codina, Anna, Passoni, Lorena, Matteoli, Michela, de la Iglesia, Nuria, Seano, Giorgio, Martínez-Soler, Fina, Tortosa, Avelina
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/49001
Acceso en línea:http://hdl.handle.net/10230/49001
http://dx.doi.org/10.3390/cancers13123055
Access Level:acceso abierto
Palabra clave:ITGA6
Cancer stem cells
Glioblastoma
Integrin alpha-6
Mesenchymal subtype
Radioresistance
Radiotherapy
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spelling Dual role of integrin Alpha-6 in glioblastoma: supporting stemness in proneural stem-like cells while inducing radioresistance in mesenchymal stem-like cellsStanzani, ElisabettaPedrosa, LeireBourmeau, GuillaumeAnezo, OceaneNoguera-Castells, AleixEsteve-Codina, AnnaPassoni, LorenaMatteoli, Michelade la Iglesia, NuriaSeano, GiorgioMartínez-Soler, FinaTortosa, AvelinaITGA6Cancer stem cellsGlioblastomaIntegrin alpha-6Mesenchymal subtypeRadioresistanceRadiotherapyTherapeutic resistance after multimodal therapy is the most relevant cause of glioblastoma (GBM) recurrence. Extensive cellular heterogeneity, mainly driven by the presence of GBM stem-like cells (GSCs), strongly correlates with patients' prognosis and limited response to therapies. Defining the mechanisms that drive stemness and control responsiveness to therapy in a GSC-specific manner is therefore essential. Here we investigated the role of integrin a6 (ITGA6) in controlling stemness and resistance to radiotherapy in proneural and mesenchymal GSCs subtypes. Using cell sorting, gene silencing, RNA-Seq, and in vitro assays, we verified that ITGA6 expression seems crucial for proliferation and stemness of proneural GSCs, while it appears not to be relevant in mesenchymal GSCs under basal conditions. However, when challenged with a fractionated protocol of radiation therapy, comparable to that used in the clinical setting, mesenchymal GSCs were dependent on integrin a6 for survival. Specifically, GSCs with reduced levels of ITGA6 displayed a clear reduction of DNA damage response and perturbation of cell cycle pathways. These data indicate that ITGA6 inhibition is able to overcome the radioresistance of mesenchymal GSCs, while it reduces proliferation and stemness in proneural GSCs. Therefore, integrin a6 controls crucial characteristics across GBM subtypes in GBM heterogeneous biology and thus may represent a promising target to improve patient outcomes.This work was supported by Agència Gestió Ajuts Universitaris i Recerca, Generalitat de Catalunya, grant number 2017SGR1014); Red Temática de investigación cooperativa en cáncer, grant number RD12/0036/0029); School of Nursing, grant number PREI-UB 17/005I; 18/010I; 19/009A; the Fondation ARC pour la recherche sur le cancer, the INSERM-CNRS ATIP-Avenir grant, the European Research Council (ERC) under the European Union’s Horizon 2020 (grant agreement no. 805225) and the NanoTheRad (Paris-Saclay University). High-throughput sequencing was performed by the ICGex platform of the Institut Curie supported by the grants ANR-10-EQPX-03, ANR-10-INBS-09-08, and INCa-DGOS-4654. Work of M.M. and L.P. is supported by Fondazione AIRC per la Ricerca sul Cancro (IG 18851). E.S. is presently supported by Fondazione Veronesi. A.E-C. is funded by ISCIII/MINECO (PT17/0009/0019) and co-funded by FEDER.MDPI202120212021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/49001http://dx.doi.org/10.3390/cancers13123055reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésCancers (Basel). 2021;13(12):3055info:eu-repo/grantAgreement/EC/H2020/805225© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/490012026-05-29T05:05:01Z
dc.title.none.fl_str_mv Dual role of integrin Alpha-6 in glioblastoma: supporting stemness in proneural stem-like cells while inducing radioresistance in mesenchymal stem-like cells
title Dual role of integrin Alpha-6 in glioblastoma: supporting stemness in proneural stem-like cells while inducing radioresistance in mesenchymal stem-like cells
spellingShingle Dual role of integrin Alpha-6 in glioblastoma: supporting stemness in proneural stem-like cells while inducing radioresistance in mesenchymal stem-like cells
Stanzani, Elisabetta
ITGA6
Cancer stem cells
Glioblastoma
Integrin alpha-6
Mesenchymal subtype
Radioresistance
Radiotherapy
title_short Dual role of integrin Alpha-6 in glioblastoma: supporting stemness in proneural stem-like cells while inducing radioresistance in mesenchymal stem-like cells
title_full Dual role of integrin Alpha-6 in glioblastoma: supporting stemness in proneural stem-like cells while inducing radioresistance in mesenchymal stem-like cells
title_fullStr Dual role of integrin Alpha-6 in glioblastoma: supporting stemness in proneural stem-like cells while inducing radioresistance in mesenchymal stem-like cells
title_full_unstemmed Dual role of integrin Alpha-6 in glioblastoma: supporting stemness in proneural stem-like cells while inducing radioresistance in mesenchymal stem-like cells
title_sort Dual role of integrin Alpha-6 in glioblastoma: supporting stemness in proneural stem-like cells while inducing radioresistance in mesenchymal stem-like cells
dc.creator.none.fl_str_mv Stanzani, Elisabetta
Pedrosa, Leire
Bourmeau, Guillaume
Anezo, Oceane
Noguera-Castells, Aleix
Esteve-Codina, Anna
Passoni, Lorena
Matteoli, Michela
de la Iglesia, Nuria
Seano, Giorgio
Martínez-Soler, Fina
Tortosa, Avelina
author Stanzani, Elisabetta
author_facet Stanzani, Elisabetta
Pedrosa, Leire
Bourmeau, Guillaume
Anezo, Oceane
Noguera-Castells, Aleix
Esteve-Codina, Anna
Passoni, Lorena
Matteoli, Michela
de la Iglesia, Nuria
Seano, Giorgio
Martínez-Soler, Fina
Tortosa, Avelina
author_role author
author2 Pedrosa, Leire
Bourmeau, Guillaume
Anezo, Oceane
Noguera-Castells, Aleix
Esteve-Codina, Anna
Passoni, Lorena
Matteoli, Michela
de la Iglesia, Nuria
Seano, Giorgio
Martínez-Soler, Fina
Tortosa, Avelina
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ITGA6
Cancer stem cells
Glioblastoma
Integrin alpha-6
Mesenchymal subtype
Radioresistance
Radiotherapy
topic ITGA6
Cancer stem cells
Glioblastoma
Integrin alpha-6
Mesenchymal subtype
Radioresistance
Radiotherapy
description Therapeutic resistance after multimodal therapy is the most relevant cause of glioblastoma (GBM) recurrence. Extensive cellular heterogeneity, mainly driven by the presence of GBM stem-like cells (GSCs), strongly correlates with patients' prognosis and limited response to therapies. Defining the mechanisms that drive stemness and control responsiveness to therapy in a GSC-specific manner is therefore essential. Here we investigated the role of integrin a6 (ITGA6) in controlling stemness and resistance to radiotherapy in proneural and mesenchymal GSCs subtypes. Using cell sorting, gene silencing, RNA-Seq, and in vitro assays, we verified that ITGA6 expression seems crucial for proliferation and stemness of proneural GSCs, while it appears not to be relevant in mesenchymal GSCs under basal conditions. However, when challenged with a fractionated protocol of radiation therapy, comparable to that used in the clinical setting, mesenchymal GSCs were dependent on integrin a6 for survival. Specifically, GSCs with reduced levels of ITGA6 displayed a clear reduction of DNA damage response and perturbation of cell cycle pathways. These data indicate that ITGA6 inhibition is able to overcome the radioresistance of mesenchymal GSCs, while it reduces proliferation and stemness in proneural GSCs. Therefore, integrin a6 controls crucial characteristics across GBM subtypes in GBM heterogeneous biology and thus may represent a promising target to improve patient outcomes.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/49001
http://dx.doi.org/10.3390/cancers13123055
url http://hdl.handle.net/10230/49001
http://dx.doi.org/10.3390/cancers13123055
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Cancers (Basel). 2021;13(12):3055
info:eu-repo/grantAgreement/EC/H2020/805225
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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