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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Riedel, Angela 
Kerr, Emma 
Pedro, Luisa 
Bihary, Dóra 

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.

Description

Keywords

Animals, Biological Transport, Embryo, Mammalian, Fibroblasts, Gene Expression Regulation, Neoplastic, Humans, Mice, Inbred C57BL, Models, Biological, Neoplasms, Osmoregulation, Phenotype, Stromal Cells

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

9

Publisher

Springer Science and Business Media LLC
Sponsorship
Royal Society (Paul Instrument Fund) (UF130039)
MRC (unknown)
Medical Research Council (MC_UU_12022/9)
MRC (MR/N501876/1)
MRC
Cancer Research UK (CB4160)
Medical Research Council (MC_UU_12022/5)
MRC (MC_UU_12022/10)
MRC (MR/N501876/1)
Royal Society, MRC