title: Oncometabolic Nuclear Reprogramming of Cancer Stemness.
abstract: 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.
authors.affiliation: ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism and Cancer Group, Catalan Institute of Oncology, 17007 Girona, Catalonia, Spain; Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), 17190 Salt, Catalonia, Spain; Girona Biomedical Research Institute (IDIBGI), Parc Hospitalari Martí i Julià, Edifici M2, E-17190 Salt, Girona, Spain. Electronic address: jmenendez@iconcologia.net.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Menendez
authors.affiliation: Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), 17190 Salt, Catalonia, Spain.
authors.forename: Bruna
authors.initials: B
authors.lastname: Corominas-Faja
authors.affiliation: Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI), 17190 Salt, Catalonia, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Cuyàs
authors.affiliation: Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA-HUCA), Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: María G
authors.initials: MG
authors.lastname: García
authors.affiliation: Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, IISPV, Universitat Rovira i Virgili, Campus of International Excellence Southern Catalonia, 43201 Reus, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Fernández-Arroyo
authors.affiliation: Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA-HUCA), Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: Agustín F
authors.initials: AF
authors.lastname: Fernández
authors.affiliation: Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, IISPV, Universitat Rovira i Virgili, Campus of International Excellence Southern Catalonia, 43201 Reus, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Joven
authors.affiliation: Cancer Epigenetics Laboratory, Instituto Universitario de Oncología del Principado de Asturias (IUOPA-HUCA), Universidad de Oviedo, 33006 Oviedo, Spain; Nanomaterials and Nanotechnology Research Center (CINN-CSIC), 33940 San Martín del Rey Aurelio, Spain.
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
authors.affiliation: Institució Catalana d'Estudis i Recerca Avançats (ICREA), 08010 Barcelona, Spain; Computational & Mathematical Biology Research Group, Centre de Recerca Matemàtica (CRM), 08193 Barcelona, Spain; Departament de Matemàtiques, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain; Barcelona Graduate School of Mathematics (BGSMath), 08193 Barcelona, Spain; Centre de Recerca Matemàtica (CRM), Office 29 (C3b/140), Edifici C, Campus de Bellaterra, E-08193 Bellaterra, Barcelona, Spain. Electronic address: talarcon@crm.cat.
authors.forename: Tomás
authors.initials: T
authors.lastname: Alarcón
mesh_terms: D065150:Cellular Reprogramming; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008745:Methylation; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism; D011499:Protein Processing, Post-Translational
chemical_list: D006657:Histones
keywords: Oncometabolites; cancer; cancer stem cells; reprogramming; stem cells; stemness