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