Viral targeting of glioblastoma stem cells with patient-specific genetic and post-translational p53 deregulations

Cancer therapy urges targeting of malignant subsets within self-renewing heterogeneous stem cell populations. We dissect the genetic and functional heterogeneity of human glioblastoma stem cells (GSCs) within patients by their innate responses to non-pathogenic mouse parvoviruses that are tightly re...

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Detalles Bibliográficos
Autores: Gil-Ranedo, Jon, Gallego-García, Carlos, Almendral, José M.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/271126
Acceso en línea:http://hdl.handle.net/10261/271126
Access Level:acceso abierto
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spelling Viral targeting of glioblastoma stem cells with patient-specific genetic and post-translational p53 deregulationsGil-Ranedo, JonGallego-García, CarlosAlmendral, José M.Cancer therapy urges targeting of malignant subsets within self-renewing heterogeneous stem cell populations. We dissect the genetic and functional heterogeneity of human glioblastoma stem cells (GSCs) within patients by their innate responses to non-pathogenic mouse parvoviruses that are tightly restrained by cellular physiology. GSC neurospheres accumulate assembled capsids but restrict viral NS1 cytotoxic protein expression by an innate PKR/eIF2α-P response counteractable by electric pulses. NS1 triggers a comprehensive DNA damage response involving cell-cycle arrest, neurosphere disorganization, and bystander disruption of GSC-derived brain tumor architecture in rodent models. GSCs and cancer cell lines permissive to parvovirus genome replication require p53-Ser15 phosphorylation (Pp53S15). NS1 expression is enhanced by exogeneous Pp53S15 induction but repressed by wtp53. Consistently, patient-specific GSC subpopulations harboring p53 gain-of-function mutants and/or Pp53S15 are selective viral targets. This study provides a molecular foundation for personalized biosafe viral therapies against devastating glioblastoma and other cancers with deregulated p53 signaling.SAF2008-03238 and SAF2011-29403 (Spanish Ministerio de Ciencia e Innovacion), S2013/ABI-2906-FEDER (Comunidad de Madrid), and SAF2015-68522-P-MINECO/FEDER,UE (Spanish Ministerio de Economía y Competitividad and Ministerio de Ciencia, Investigación y Universidades) to J.M.A. The Centro de Biología Molecular Severo Ochoa (CSIC-UAM) is, in part, supported by institutional grants from Banco Santander and Fundación Ramón Areces.Ministerio de Ciencia e Innovación (España)Comunidad de MadridMinisterio de Economía y Competitividad (España)Ministerio de Ciencia, Innovación y Universidades (España)Banco SantanderFundación Ramón ArecesConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2022202220212022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/271126reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1016/j.celrep.2021.109673Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2711262026-05-22T06:33:51Z
dc.title.none.fl_str_mv Viral targeting of glioblastoma stem cells with patient-specific genetic and post-translational p53 deregulations
title Viral targeting of glioblastoma stem cells with patient-specific genetic and post-translational p53 deregulations
spellingShingle Viral targeting of glioblastoma stem cells with patient-specific genetic and post-translational p53 deregulations
Gil-Ranedo, Jon
title_short Viral targeting of glioblastoma stem cells with patient-specific genetic and post-translational p53 deregulations
title_full Viral targeting of glioblastoma stem cells with patient-specific genetic and post-translational p53 deregulations
title_fullStr Viral targeting of glioblastoma stem cells with patient-specific genetic and post-translational p53 deregulations
title_full_unstemmed Viral targeting of glioblastoma stem cells with patient-specific genetic and post-translational p53 deregulations
title_sort Viral targeting of glioblastoma stem cells with patient-specific genetic and post-translational p53 deregulations
dc.creator.none.fl_str_mv Gil-Ranedo, Jon
Gallego-García, Carlos
Almendral, José M.
author Gil-Ranedo, Jon
author_facet Gil-Ranedo, Jon
Gallego-García, Carlos
Almendral, José M.
author_role author
author2 Gallego-García, Carlos
Almendral, José M.
author2_role author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia e Innovación (España)
Comunidad de Madrid
Ministerio de Economía y Competitividad (España)
Ministerio de Ciencia, Innovación y Universidades (España)
Banco Santander
Fundación Ramón Areces
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description Cancer therapy urges targeting of malignant subsets within self-renewing heterogeneous stem cell populations. We dissect the genetic and functional heterogeneity of human glioblastoma stem cells (GSCs) within patients by their innate responses to non-pathogenic mouse parvoviruses that are tightly restrained by cellular physiology. GSC neurospheres accumulate assembled capsids but restrict viral NS1 cytotoxic protein expression by an innate PKR/eIF2α-P response counteractable by electric pulses. NS1 triggers a comprehensive DNA damage response involving cell-cycle arrest, neurosphere disorganization, and bystander disruption of GSC-derived brain tumor architecture in rodent models. GSCs and cancer cell lines permissive to parvovirus genome replication require p53-Ser15 phosphorylation (Pp53S15). NS1 expression is enhanced by exogeneous Pp53S15 induction but repressed by wtp53. Consistently, patient-specific GSC subpopulations harboring p53 gain-of-function mutants and/or Pp53S15 are selective viral targets. This study provides a molecular foundation for personalized biosafe viral therapies against devastating glioblastoma and other cancers with deregulated p53 signaling.
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
2022
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
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/271126
url http://hdl.handle.net/10261/271126
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1016/j.celrep.2021.109673
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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