Exploring the role of stromal osmoregulation in cancer and disease using executable modelling

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    • David Shorthouse
    • Angela Reidel
    • Emma Kerr
    • Luisa Pedro
    • Dora Bihary
    • Shamith Samarajiwa
    • Carla Martins
    • Jacqueline Shields
    • Ben Hall

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    Osmotic regulation is a vital homoeostatic 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.

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    • Exploring the role of stromal osmoregulation in cancer and disease using executable modelling

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    DOI

    Original languageEnglish
    Article number3011
    Number of pages15
    JournalNature Communications
    Journal publication date01 Aug 2018
    Volume9
    DOIs
    Publication statusPublished - 01 Aug 2018
    Externally publishedYes

    ID: 166172304