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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Authors: Menéndez, Javier A.|||0000-0001-8733-4561, Corominas-Faja, Bruna, Cuyàs, Elisabet|||0000-0001-5353-440X, García, María G., Fernández-Arroyo, Salvador, Fernández, Agustín F.|||0000-0002-3792-4085, Joven, Jorge|||0000-0003-2749-4541, Fraga, Mario|||0000-0001-8450-2603, Alarcón Cor, Tomás|||0000-0002-8566-3676
Format: article
Publication Date:2016
Country:España
Institution:Universitat Autònoma de Barcelona
Repository:Dipòsit Digital de Documents de la UAB
Language:English
OAI Identifier:oai:ddd.uab.cat:185791
Online Access:https://ddd.uab.cat/record/185791
https://dx.doi.org/urn:doi:10.1016/j.stemcr.2015.12.012
Access Level:Open access
Keyword:Oncometabolites
Reprogramming
Stemness
Cancer
Stem cells
Cancer stem cells
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spelling Oncometabolic nuclear reprogramming of cancer stemnessMenéndez, Javier A.|||0000-0001-8733-4561Corominas-Faja, BrunaCuyàs, Elisabet|||0000-0001-5353-440XGarcía, María G.Fernández-Arroyo, SalvadorFernández, Agustín F.|||0000-0002-3792-4085Joven, Jorge|||0000-0003-2749-4541Fraga, Mario|||0000-0001-8450-2603Alarcón Cor, Tomás|||0000-0002-8566-3676OncometabolitesReprogrammingStemnessCancerStem 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. Using a systems biology approach combining mathematical and computational modeling with proof-of-concept experiments in cultured cells, Menendez and colleagues provide evidence that oncometabolic versions of nuclear reprogramming phenomena are capable of generating cancer stem-like states from more differentiated counterparts. These findings offer an innovative stochastic modeling tool as well as a conceptual framework for investigating the underexplored link between cellular metabolism and cancer-initiating alterations of the epigenome at the stem cell level. 22016-01-0120162016-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/185791https://dx.doi.org/urn:doi:10.1016/j.stemcr.2015.12.012reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengMinisterio de Ciencia e Innovación https://doi.org/10.13039/501100004837 SAF2012-3891Ministerio de Ciencia e Innovación https://doi.org/10.13039/501100004837 MTM2011-29342Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2014/SGR-1307Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2014/SGR-229open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:1857912026-06-06T12:50:31Z
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.|||0000-0001-8733-4561
Oncometabolites
Reprogramming
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.|||0000-0001-8733-4561
Corominas-Faja, Bruna
Cuyàs, Elisabet|||0000-0001-5353-440X
García, María G.
Fernández-Arroyo, Salvador
Fernández, Agustín F.|||0000-0002-3792-4085
Joven, Jorge|||0000-0003-2749-4541
Fraga, Mario|||0000-0001-8450-2603
Alarcón Cor, Tomás|||0000-0002-8566-3676
author Menéndez, Javier A.|||0000-0001-8733-4561
author_facet Menéndez, Javier A.|||0000-0001-8733-4561
Corominas-Faja, Bruna
Cuyàs, Elisabet|||0000-0001-5353-440X
García, María G.
Fernández-Arroyo, Salvador
Fernández, Agustín F.|||0000-0002-3792-4085
Joven, Jorge|||0000-0003-2749-4541
Fraga, Mario|||0000-0001-8450-2603
Alarcón Cor, Tomás|||0000-0002-8566-3676
author_role author
author2 Corominas-Faja, Bruna
Cuyàs, Elisabet|||0000-0001-5353-440X
García, María G.
Fernández-Arroyo, Salvador
Fernández, Agustín F.|||0000-0002-3792-4085
Joven, Jorge|||0000-0003-2749-4541
Fraga, Mario|||0000-0001-8450-2603
Alarcón Cor, Tomás|||0000-0002-8566-3676
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Oncometabolites
Reprogramming
Stemness
Cancer
Stem cells
Cancer stem cells
topic Oncometabolites
Reprogramming
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. Using a systems biology approach combining mathematical and computational modeling with proof-of-concept experiments in cultured cells, Menendez and colleagues provide evidence that oncometabolic versions of nuclear reprogramming phenomena are capable of generating cancer stem-like states from more differentiated counterparts. These findings offer an innovative stochastic modeling tool as well as a conceptual framework for investigating the underexplored link between cellular metabolism and cancer-initiating alterations of the epigenome at the stem cell level.
publishDate 2016
dc.date.none.fl_str_mv 2
2016-01-01
2016
2016-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/185791
https://dx.doi.org/urn:doi:10.1016/j.stemcr.2015.12.012
url https://ddd.uab.cat/record/185791
https://dx.doi.org/urn:doi:10.1016/j.stemcr.2015.12.012
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Ministerio de Ciencia e Innovación https://doi.org/10.13039/501100004837 SAF2012-3891
Ministerio de Ciencia e Innovación https://doi.org/10.13039/501100004837 MTM2011-29342
Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2014/SGR-1307
Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2014/SGR-229
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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