Exploring the role of stromal osmoregulation in cancer and disease using executable modelling.
Pedro Martins, Carla
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Shorthouse, D., Riedel, A., Kerr, E., Pedro, L., Bihary, D., Samarajiwa, S., Pedro Martins, C., et al. (2018). Exploring the role of stromal osmoregulation in cancer and disease using executable modelling.. Nature communications, 9 (1), 3011. https://doi.org/10.1038/s41467-018-05414-y
Osmotic regulation is a vital homeostatic process in all cells and tissues. Cells initially respond to osmotic stresses by activating transmembrane transport proteins to move osmotically active ions. Disruption of ion and water transport is frequently observed in cellular transformations such as cancer. We report that genes involved in membrane transport are significantly deregulated in many cancers, and that their expression can distinguish cancer cells from normal cells with a high degree of accuracy. We present an executable model of osmotic regulation and membrane transport in mammalian cells, providing a mechanistic explanation for phenotype change in varied disease states, and accurately predicting behaviour from single cell expression data. We also predict key proteins involved in cellular transformation, SLC4A3 (AE3), and SLC9A1 (NHE1). Furthermore, we predict and verify a synergistic drug combination in vitro, of sodium and chloride channel inhibitors, which target the osmoregulatory network to reduce cancer-associated phenotypes in fibroblasts.
Fibroblasts, Stromal Cells, Animals, Mice, Inbred C57BL, Humans, Neoplasms, Gene Expression Regulation, Neoplastic, Biological Transport, Phenotype, Models, Biological, Embryo, Mammalian, Osmoregulation
Royal Society, MRC
Royal Society (Paul Instrument Fund) (UF130039)
Medical Research Council (MC_UU_12022/9)
Cancer Research UK (CB4160)
External DOI: https://doi.org/10.1038/s41467-018-05414-y
This record's URL: https://www.repository.cam.ac.uk/handle/1810/284139
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/