A RAC-GEF network critical for early intestinal tumourigenesis
Authors
Pickering, K. A.
Gilroy, K.
Cassidy, J. W.
Fey, S. K.
Vincent, D. F.
Johansson, J.
Fordham, R. P.
Miller, B.
Clark, W.
Hedley, A.
Unal, E. B.
Kiel, C.
McGhee, E.
Bain, M.
van Hoof, S. R.
Medema, J. P.
Brachmann, S. M.
Stucke, V. M.
Drysdale, M.
Publication Date
2021-01-04Journal Title
Nature Communications
Publisher
Nature Publishing Group UK
Volume
12
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Pickering, K. A., Gilroy, K., Cassidy, J. W., Fey, S. K., Najumudeen, A. K., Zeiger, L. B., Vincent, D. F., et al. (2021). A RAC-GEF network critical for early intestinal tumourigenesis. Nature Communications, 12 (1) https://doi.org/10.1038/s41467-020-20255-4
Abstract
Abstract: RAC1 activity is critical for intestinal homeostasis, and is required for hyperproliferation driven by loss of the tumour suppressor gene Apc in the murine intestine. To avoid the impact of direct targeting upon homeostasis, we reasoned that indirect targeting of RAC1 via RAC-GEFs might be effective. Transcriptional profiling of Apc deficient intestinal tissue identified Vav3 and Tiam1 as key targets. Deletion of these indicated that while TIAM1 deficiency could suppress Apc-driven hyperproliferation, it had no impact upon tumourigenesis, while VAV3 deficiency had no effect. Intriguingly, deletion of either gene resulted in upregulation of Vav2, with subsequent targeting of all three (Vav2−/−Vav3−/−Tiam1−/−), profoundly suppressing hyperproliferation, tumourigenesis and RAC1 activity, without impacting normal homeostasis. Critically, the observed RAC-GEF dependency was negated by oncogenic KRAS mutation. Together, these data demonstrate that while targeting RAC-GEF molecules may have therapeutic impact at early stages, this benefit may be lost in late stage disease.
Keywords
Article, /631/67/70, /631/67/1504/1885/1393, /38/91, /13/51, /13/106, /14/33, /64/60, article
Identifiers
s41467-020-20255-4, 20255
External DOI: https://doi.org/10.1038/s41467-020-20255-4
This record's URL: https://www.repository.cam.ac.uk/handle/1810/315657
Rights
Attribution 4.0 International (CC BY 4.0)
Licence URL: https://creativecommons.org/licenses/by/4.0/
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