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; 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

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

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dc.contributor.author Stanzani, Elisabetta
dc.contributor.author Pedrosa, Leire
dc.contributor.author Bourmeau, Guillaume
dc.contributor.author Anezo, Oceane
dc.contributor.author Noguera-Castells, Aleix
dc.contributor.author Esteve-Codina, Anna
dc.contributor.author Passoni, Lorena
dc.contributor.author Matteoli, Michela
dc.contributor.author de la Iglesia, Nuria
dc.contributor.author Seano, Giorgio
dc.contributor.author Martínez-Soler, Fina
dc.contributor.author Tortosa, Avelina
dc.date.accessioned 2021-11-17T07:39:43Z
dc.date.available 2021-11-17T07:39:43Z
dc.date.issued 2021
dc.description.abstract 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.
dc.description.sponsorship 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.
dc.format.mimetype application/pdf
dc.identifier.citation Stanzani E, Pedrosa L, Bourmeau G, Anezo O, Noguera-Castells A, Esteve-Codina A, Passoni L, Matteoli M, de la Iglesia N, Seano G, Martínez-Soler F, Tortosa A. Dual role of integrin Alpha-6 in glioblastoma: supporting stemness in proneural stem-like cells while inducing radioresistance in mesenchymal stem-like cells. Cancers (Basel). 2021;13(12):3055. DOI: 10.3390/cancers13123055
dc.identifier.doi http://dx.doi.org/10.3390/cancers13123055
dc.identifier.issn 2072-6694
dc.identifier.uri http://hdl.handle.net/10230/49001
dc.language.iso eng
dc.publisher MDPI
dc.relation.ispartof Cancers (Basel). 2021;13(12):3055
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/805225
dc.rights © 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/).
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword ITGA6
dc.subject.keyword Cancer stem cells
dc.subject.keyword Glioblastoma
dc.subject.keyword Integrin alpha-6
dc.subject.keyword Mesenchymal subtype
dc.subject.keyword Radioresistance
dc.subject.keyword Radiotherapy
dc.title Dual role of integrin Alpha-6 in glioblastoma: supporting stemness in proneural stem-like cells while inducing radioresistance in mesenchymal stem-like cells
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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