Exploring the role of stromal osmoregulation in cancer and disease using executable modelling.
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Authors
Riedel, Angela
Kerr, Emma
Bihary, Dóra
Pedro Martins, Carla
Shields, Jacqueline
Publication Date
2018-08Journal Title
Nature communications
ISSN
2041-1723
Publisher
Springer Nature
Volume
9
Issue
1
Pages
3011
Language
eng
Type
Article
Physical Medium
Electronic
Metadata
Show full item recordCitation
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
Abstract
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.
Keywords
Fibroblasts, Stromal Cells, Animals, Mice, Inbred C57BL, Humans, Neoplasms, Gene Expression Regulation, Neoplastic, Biological Transport, Phenotype, Models, Biological, Embryo, Mammalian, Osmoregulation
Sponsorship
Royal Society, MRC
Funder references
Royal Society (Paul Instrument Fund) (UF130039)
MRC (MC_UU_12022/1_do not transfer?)
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)
Identifiers
External DOI: https://doi.org/10.1038/s41467-018-05414-y
This record's URL: https://www.repository.cam.ac.uk/handle/1810/284139