A RAC-GEF network critical for early intestinal tumourigenesis
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- dc.contributor.author Pickering, Karen
- dc.contributor.author Unal, E. Besray
- dc.contributor.author Kiel, Christina
- dc.contributor.author Serrano Pubull, Luis, 1982-
- dc.contributor.author Sansom, Owen J.
- dc.date.accessioned 2022-05-20T05:52:09Z
- dc.date.available 2022-05-20T05:52:09Z
- dc.date.issued 2021
- dc.description.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.
- dc.description.sponsorship Funding: R.P.F was funded through a fellowship from the Royal Commission for the Exhibition of 1851. A.K.N. and L.B.Z. are funded through CRUK Grand Challenge Rosetta (A25045). S.K.F. is funded through the PCUK Future Leaders Academy (2017FutureLeadersAcademy). K.G. is funded through CRUK Grand Challenge Specificancer (A29055). L.M.M., M.B., K.I.A., M.D. and O.J.S. are supported through CRUK (A15673, A15565, A17096, A21139 and A17196 respectively). A.K.J. and M.T. are supported by BBSRC. D.M.G. and O.J.S. were also funded through ERC ColonCan (ERC starting grant 311301). Additionally, K.A.P., A.D.C., D.M.G., J.J., R.P.F., B.M., W.C., A.H., E.M., L.M.M., C.N., D.S., K.I.A., M.D. and O.J.S. are supported by CRUK Beatson core funding (A17196)
- dc.format.mimetype application/pdf
- dc.identifier.citation Pickering KA, Gilroy K, Cassidy JW, Fey SK, Najumudeen AK, Zeiger LB et al. A RAC-GEF network critical for early intestinal tumourigenesis. Nat Commun. 2021 Jan 4;12(1):56. DOI:10.1038/s41467-020-20255-4
- dc.identifier.doi http://dx.doi.org/10.1038/s41467-020-20255-4
- dc.identifier.issn 2041-1723
- dc.identifier.uri http://hdl.handle.net/10230/53177
- dc.language.iso eng
- dc.publisher Nature Research
- dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/311301
- dc.rights © K. A. Pickering et al. 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri https://creativecommons.org/licenses/by/4.0/
- dc.subject.other Intestins -- Càncer
- dc.subject.other Tumors
- dc.subject.other Homeòstasi
- dc.subject.other Genètica
- dc.title A RAC-GEF network critical for early intestinal tumourigenesis
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion