RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness

© 2021 The Authors.

Detalles Bibliográficos
Autores: Benítez, Sandra, Cordero, Alex, Santamaría, Patricia G., Redondo-Pedraza, Jaime, Rocha, Ana S., Collado-Solé, Alejandro, Jiménez, María, Sanz-Moreno, Adrián, Yoldi, Guillermo, Santos, Juliana C., Benedictis, Ilaria De, Gómez-Aleza, Clara, Silva-Alvarez, S. da, Troulé, Kevin, Gómez-López, Gonzalo, Alcázar, Noelia, Palmero, Ignacio, Collado, Manuel, Serrano, Manuel, González-Suarez, Eva
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:10261/265429
Acceso en línea:http://hdl.handle.net/10261/265429
Access Level:acceso abierto
Palabra clave:Breast cancer
Mammary gland
Receptor activator of NFkB
Senescence
Senolytics
Stemness
Metastasis
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spelling RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressivenessBenítez, SandraCordero, AlexSantamaría, Patricia G.Redondo-Pedraza, JaimeRocha, Ana S.Collado-Solé, AlejandroJiménez, MaríaSanz-Moreno, AdriánYoldi, GuillermoSantos, Juliana C.Benedictis, Ilaria DeGómez-Aleza, ClaraSilva-Alvarez, S. daTroulé, KevinGómez-López, GonzaloAlcázar, NoeliaPalmero, IgnacioCollado, ManuelSerrano, ManuelGonzález-Suarez, EvaBreast cancerMammary glandReceptor activator of NFkBSenescenceSenolyticsStemnessMetastasis© 2021 The Authors.Rank signaling enhances stemness in mouse and human mammary epithelial cells (MECs) and mediates mammary tumor initiation. Mammary tumors initiated by oncogenes or carcinogen exposure display high levels of Rank and Rank pathway inhibitors have emerged as a new strategy for breast cancer prevention and treatment. Here, we show that ectopic Rank expression in the mammary epithelia unexpectedly delays tumor onset and reduces tumor incidence in the oncogene-driven Neu and PyMT models. Mechanistically, we have found that ectopic expression of Rank or exposure to Rankl induces senescence, even in the absence of other oncogenic mutations. Rank leads to DNA damage and senescence through p16/p19. Moreover, RANK-induced senescence is essential for Rank-driven stemness, and although initially translates into delayed tumor growth, eventually promotes tumor progression and metastasis. We uncover a dual role for Rank in the mammary epithelia: Rank induces senescence and stemness, delaying tumor initiation but increasing tumor aggressiveness.This work was supported by grants to E. González-Suárez by the Agencia Estatal de Investigación (AEI) (SAF2014-55997-R, SAF2017-86117-R) co-funded by FEDER funds/European Regional Development Fund (ERDF) (a way to build Europe), by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 682935), and by the Fundació La Marató de TV3. We thank CERCA Programme/Generalitat de Catalunya for institutional support. S. Benítez was a recipient of an FPI, A. Collado-Solé holds an FPU from the MICINN and J Redondo-Pedraza is a recipient of an FPI Severo Ochoa Fellowship. We are grateful to Amgen for providing Rankl and Rankt+/tg mice.ElsevierMinisterio de Economía y Competitividad (España)Ministerio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)European CommissionEuropean Research CouncilEuropean CommissionFundació La Marató de TV3Generalitat de CatalunyaConsejo 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/10261/265429reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO//SAF2014-55997-Rinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-86117-Rinfo:eu-repo/grantAgreement/EC/H2020/682935http://dx.doi.org/10.1016/j.devcel.2021.04.022Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2654292026-05-22T06:33:51Z
dc.title.none.fl_str_mv RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness
title RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness
spellingShingle RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness
Benítez, Sandra
Breast cancer
Mammary gland
Receptor activator of NFkB
Senescence
Senolytics
Stemness
Metastasis
title_short RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness
title_full RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness
title_fullStr RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness
title_full_unstemmed RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness
title_sort RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness
dc.creator.none.fl_str_mv Benítez, Sandra
Cordero, Alex
Santamaría, Patricia G.
Redondo-Pedraza, Jaime
Rocha, Ana S.
Collado-Solé, Alejandro
Jiménez, María
Sanz-Moreno, Adrián
Yoldi, Guillermo
Santos, Juliana C.
Benedictis, Ilaria De
Gómez-Aleza, Clara
Silva-Alvarez, S. da
Troulé, Kevin
Gómez-López, Gonzalo
Alcázar, Noelia
Palmero, Ignacio
Collado, Manuel
Serrano, Manuel
González-Suarez, Eva
author Benítez, Sandra
author_facet Benítez, Sandra
Cordero, Alex
Santamaría, Patricia G.
Redondo-Pedraza, Jaime
Rocha, Ana S.
Collado-Solé, Alejandro
Jiménez, María
Sanz-Moreno, Adrián
Yoldi, Guillermo
Santos, Juliana C.
Benedictis, Ilaria De
Gómez-Aleza, Clara
Silva-Alvarez, S. da
Troulé, Kevin
Gómez-López, Gonzalo
Alcázar, Noelia
Palmero, Ignacio
Collado, Manuel
Serrano, Manuel
González-Suarez, Eva
author_role author
author2 Cordero, Alex
Santamaría, Patricia G.
Redondo-Pedraza, Jaime
Rocha, Ana S.
Collado-Solé, Alejandro
Jiménez, María
Sanz-Moreno, Adrián
Yoldi, Guillermo
Santos, Juliana C.
Benedictis, Ilaria De
Gómez-Aleza, Clara
Silva-Alvarez, S. da
Troulé, Kevin
Gómez-López, Gonzalo
Alcázar, Noelia
Palmero, Ignacio
Collado, Manuel
Serrano, Manuel
González-Suarez, Eva
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
European Commission
European Research Council
European Commission
Fundació La Marató de TV3
Generalitat de Catalunya
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Breast cancer
Mammary gland
Receptor activator of NFkB
Senescence
Senolytics
Stemness
Metastasis
topic Breast cancer
Mammary gland
Receptor activator of NFkB
Senescence
Senolytics
Stemness
Metastasis
description © 2021 The Authors.
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/10261/265429
url http://hdl.handle.net/10261/265429
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO//SAF2014-55997-R
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-86117-R
info:eu-repo/grantAgreement/EC/H2020/682935
http://dx.doi.org/10.1016/j.devcel.2021.04.022
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
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)
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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