Oncometabolic nuclear reprogramming of cancer stemness
Menendez, Javier A. (Institut Català d'Oncologia)
Corominas-Faja, Bruna (Institut d'Investigació Biomèdica de Girona)
Cuyàs, Elisabet (Institut d'Investigació Biomèdica de Girona)
García, María G. (Instituto Universitario de Oncología del Principado de Asturias)
Fernández-Arroyo, Salvador (Hospital Universitari de Sant Joan)
Fernández, Agustín F. (Instituto Universitario de Oncología del Principado de Asturias)
Joven, Jorge (Hospital Universitari de Sant Joan)
Fraga, Mario F.. (Instituto Universitario de Oncología del Principado de Asturias)
Alarcón Cor, Tomás (Centre de Recerca Matemàtica)

Data:	2016
Resum:	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.
Ajuts:	Ministerio de Ciencia e Innovación SAF2012-3891 Ministerio de Ciencia e Innovación MTM2011-29342 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014/SGR-1307 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014/SGR-229
Drets:	Aquest 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.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Oncometabolites ; Reprogramming ; Stemness ; Cancer ; Stem cells ; Cancer stem cells
Publicat a:	Stem cell reports, Vol. 6, issue 3 (March 2016) , p. 273-283, ISSN 2213-6711

DOI: 10.1016/j.stemcr.2015.12.012
PMID: 26876667

11 p, 2.4 MB

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