Oncometabolic nuclear reprogramming of cancer stemness

By impairing histone demethylation and locking cells into a reprogramming-prone state, oncometabolites can partially mimic the process of induced pluripotent stem cell generation. Using a systems biology approach, combining mathematical modeling, computation, and proof-of-concept studies with live c...

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Autores: Menéndez, Javier A., Corominas-Faja, Bruna, Cuyàs, Elisabet, García, María G., Fernández-Arroyo, Salvador, Fernández, Agustín F., Joven, Jorge, Fraga, Mario F., Alarcón, Tomás
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2016
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/173234
Acceso en línea:http://hdl.handle.net/10261/173234
Access Level:acceso abierto
Palabra clave:Reprogramming
Oncometabolites
Stemness
Cancer
Stem cells
Cancer stem cells
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spelling Oncometabolic nuclear reprogramming of cancer stemnessMenéndez, Javier A.Corominas-Faja, BrunaCuyàs, ElisabetGarcía, María G.Fernández-Arroyo, SalvadorFernández, Agustín F.Joven, JorgeFraga, Mario F.Alarcón, TomásReprogrammingOncometabolitesStemnessCancerStem cellsCancer stem cellsBy impairing histone demethylation and locking cells into a reprogramming-prone state, oncometabolites can partially mimic the process of induced pluripotent stem cell generation. Using a systems biology approach, combining mathematical modeling, computation, and proof-of-concept studies with live cells, we found that an oncometabolite-driven pathological version of nuclear reprogramming increases the speed and efficiency of dedifferentiating committed epithelial cells into stem-like states with only a minimal core of stemness transcription factors. Our biomathematical model, which introduces nucleosome modification and epigenetic regulation of cell differentiation genes to account for the direct effects of oncometabolites on nuclear reprogramming, demonstrates that oncometabolites markedly lower the >energy barriers> separating non-stem and stem cell attractors, diminishes the average time of nuclear reprogramming, and increases the size of the basin of attraction of the macrostate occupied by stem cells. These findings establish the concept of oncometabolic nuclear reprogramming of stemness as a bona fide metabolo-epigenetic mechanism for generation of cancer stem-like cells.This work was supported by grants from the Ministerio de Ciencia e Innovación (Grant SAF2012-38914), Plan Nacional de I + D + I, Spain and the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (Grant 2014 SGR229), Departament d’Economia i Coneixement, Catalonia, Spain to J.A.M. T.A. acknowledges financial support from the Ministerio de Ciencia e Innovación (MICINN) under grant MTM2011-29342 and Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) under grant 2014SGR1307.Peer ReviewedElsevierMinisterio de Ciencia e Innovación (España)Generalitat de CatalunyaConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2018201820162018info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/173234reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.1016/j.stemcr.2015.12.012Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1732342026-05-22T06:33:51Z
dc.title.none.fl_str_mv Oncometabolic nuclear reprogramming of cancer stemness
title Oncometabolic nuclear reprogramming of cancer stemness
spellingShingle Oncometabolic nuclear reprogramming of cancer stemness
Menéndez, Javier A.
Reprogramming
Oncometabolites
Stemness
Cancer
Stem cells
Cancer stem cells
title_short Oncometabolic nuclear reprogramming of cancer stemness
title_full Oncometabolic nuclear reprogramming of cancer stemness
title_fullStr Oncometabolic nuclear reprogramming of cancer stemness
title_full_unstemmed Oncometabolic nuclear reprogramming of cancer stemness
title_sort Oncometabolic nuclear reprogramming of cancer stemness
dc.creator.none.fl_str_mv Menéndez, Javier A.
Corominas-Faja, Bruna
Cuyàs, Elisabet
García, María G.
Fernández-Arroyo, Salvador
Fernández, Agustín F.
Joven, Jorge
Fraga, Mario F.
Alarcón, Tomás
author Menéndez, Javier A.
author_facet Menéndez, Javier A.
Corominas-Faja, Bruna
Cuyàs, Elisabet
García, María G.
Fernández-Arroyo, Salvador
Fernández, Agustín F.
Joven, Jorge
Fraga, Mario F.
Alarcón, Tomás
author_role author
author2 Corominas-Faja, Bruna
Cuyàs, Elisabet
García, María G.
Fernández-Arroyo, Salvador
Fernández, Agustín F.
Joven, Jorge
Fraga, Mario F.
Alarcón, Tomás
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia e Innovación (España)
Generalitat de Catalunya
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Reprogramming
Oncometabolites
Stemness
Cancer
Stem cells
Cancer stem cells
topic Reprogramming
Oncometabolites
Stemness
Cancer
Stem cells
Cancer stem cells
description By impairing histone demethylation and locking cells into a reprogramming-prone state, oncometabolites can partially mimic the process of induced pluripotent stem cell generation. Using a systems biology approach, combining mathematical modeling, computation, and proof-of-concept studies with live cells, we found that an oncometabolite-driven pathological version of nuclear reprogramming increases the speed and efficiency of dedifferentiating committed epithelial cells into stem-like states with only a minimal core of stemness transcription factors. Our biomathematical model, which introduces nucleosome modification and epigenetic regulation of cell differentiation genes to account for the direct effects of oncometabolites on nuclear reprogramming, demonstrates that oncometabolites markedly lower the >energy barriers> separating non-stem and stem cell attractors, diminishes the average time of nuclear reprogramming, and increases the size of the basin of attraction of the macrostate occupied by stem cells. These findings establish the concept of oncometabolic nuclear reprogramming of stemness as a bona fide metabolo-epigenetic mechanism for generation of cancer stem-like cells.
publishDate 2016
dc.date.none.fl_str_mv 2016
2018
2018
2018
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/10261/173234
url http://hdl.handle.net/10261/173234
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.1016/j.stemcr.2015.12.012
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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score 15,812429

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