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Author Spotlight: Transmitochondrial Cybrid Generation Using Cancer Cell Lines
Published on: March 17, 2023
Oncometabolic Nuclear Reprogramming of Cancer Stemness
Javier A Menendez1, Bruna Corominas-Faja2, Elisabet Cuyàs2
1ProCURE (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.
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.
Insights
Oncometabolites accelerate cell dedifferentiation into stem-like states by altering epigenetic regulation. This metabolo-epigenetic mechanism, termed oncometabolic reprogramming, generates cancer stem-like cells.
Area of Science:
- Metabolic regulation of epigenetics
- Cancer stem cell biology
- Cellular reprogramming
Background:
- Oncometabolites can induce a reprogramming-prone cellular state.
- Cellular reprogramming is key to generating induced pluripotent stem cells.
- Understanding cancer stem cell generation is crucial for oncology.
Purpose of the Study:
- To investigate the role of oncometabolites in pathological nuclear reprogramming.
- To elucidate the metabolo-epigenetic mechanisms driving cancer stem cell formation.
- To model the impact of oncometabolites on cell differentiation and stemness.
Main Methods:
- Systems biology approach integrating mathematical modeling and computation.
- Proof-of-concept studies using live cell experiments.
- Biomathematical modeling of nucleosome modification and epigenetic regulation.
Main Results:
- Oncometabolites accelerate and enhance the dedifferentiation of epithelial cells into stem-like states.
- The biomathematical model demonstrates oncometabolites lower energy barriers between cell states.
- Oncometabolites reduce reprogramming time and increase the stem cell attractor basin size.
Conclusions:
- Oncometabolic nuclear reprogramming is a novel metabolo-epigenetic mechanism.
- This process contributes to the generation of cancer stem-like cells.
- Findings provide insights into cancer development and potential therapeutic targets.
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