Oncometabolic Nuclear Reprogramming of Cancer Stemness

Javier A. Menendez, Bruna Corominas-Faja, Elisabet Cuyàs, María G. García, Salvador Fernández-Arroyo, Agustín F. Fernández, Jorge Joven, Mario F. Fraga, Tomás Alarcón

    Research output: Contribution to journalArticleResearchpeer-review

    22 Citations (Scopus)

    Abstract

    © 2016 The Authors. 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.
    Original languageEnglish
    Pages (from-to)273-283
    JournalStem Cell Reports
    Volume6
    Issue number3
    DOIs
    Publication statusPublished - 8 Mar 2016

    Keywords

    • Oncometabolites
    • cancer
    • cancer stem cells
    • reprogramming
    • stem cells
    • stemness

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