Systematic diet composition swap in a mouse genome-scale metabolic model reveals determinants of obesogenic diet metabolism in liver cancer
Frederick Clasen,
Patrícia M. Nunes,
Gholamreza Bidkhori,
Nourdine Bah,
Stefan Boeing,
Saeed Shoaie,
Dimitrios Anastasiou
Affiliations
Frederick Clasen
Cancer Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK
Patrícia M. Nunes
Cancer Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
Gholamreza Bidkhori
Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK
Nourdine Bah
Bioinformatics and Biostatistics Science Technology Platform, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
Stefan Boeing
Bioinformatics and Biostatistics Science Technology Platform, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
Saeed Shoaie
Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK; Science for Life Laboratory (SciLifeLab), KTH - Royal Institute of Technology, Tomtebodavägen 23, 171 65 Solna, Stockholm, Sweden; Corresponding author
Dimitrios Anastasiou
Cancer Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Corresponding author
Summary: Dietary nutrient availability and gene expression, together, influence tissue metabolic activity. Here, we explore whether altering dietary nutrient composition in the context of mouse liver cancer suffices to overcome chronic gene expression changes that arise from tumorigenesis and western-style diet (WD). We construct a mouse genome-scale metabolic model and estimate metabolic fluxes in liver tumors and non-tumoral tissue after computationally varying the composition of input diet. This approach, called Systematic Diet Composition Swap (SyDiCoS), revealed that, compared to a control diet, WD increases production of glycerol and succinate irrespective of specific tissue gene expression patterns. Conversely, differences in fatty acid utilization pathways between tumor and non-tumor liver are amplified with WD by both dietary carbohydrates and lipids together. Our data suggest that combined dietary component modifications may be required to normalize the distinctive metabolic patterns that underlie selective targeting of tumor metabolism.
