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

David Shorthouse, Angela Riedel, Emma Kerr, Luisa Pedro, Dóra Bihary, Shamith Samarajiwa, Carla P. Martins, Jacqueline Shields () and Benjamin A. Hall ()
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David Shorthouse: University of Cambridge, Hutchison/MRC Research Centre
Angela Riedel: University of Cambridge, Hutchison/MRC Research Centre
Emma Kerr: University of Cambridge, Hutchison/MRC Research Centre
Luisa Pedro: University of Cambridge, Hutchison/MRC Research Centre
Dóra Bihary: University of Cambridge, Hutchison/MRC Research Centre
Shamith Samarajiwa: University of Cambridge, Hutchison/MRC Research Centre
Carla P. Martins: University of Cambridge, Hutchison/MRC Research Centre
Jacqueline Shields: University of Cambridge, Hutchison/MRC Research Centre
Benjamin A. Hall: University of Cambridge, Hutchison/MRC Research Centre

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-05414-y

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