A RAC-GEF network critical for early intestinal tumourigenesis

Pickering, K.A. et al. (2021) A RAC-GEF network critical for early intestinal tumourigenesis. Nature Communications, 12, 56. (doi: 10.1038/s41467-020-20255-4) (PMID:33397922) (PMCID:PMC7782582)

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.

• Item Type: Articles
• Additional Information: All authors are supported by Cancer Research UK. K.A.P. and A.D.C. are funded through a collaboration with Novartis and 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. M.B. is supported by University of Glasgow. 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).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Drysdale, Professor Martin and Machesky, Professor Laura and Clark, Mr William and Fey, Sigrid and Cassidy, Professor James and Bain, Professor Maureen and Zeiger, Lucas and Gilroy, Dr Kathryn and McGhee, Dr Ewan and Gay, David and Vincent, Dr David and Nixon, Miss Catherine and Myant, Dr Kevin and Strathdee, Mr Douglas and Sansom, Professor Owen and Campbell, Dr Andrew
• Authors: Pickering, K.A., Gilroy, K., Cassidy, J. W., Fey, S. K., Najumudeen, A. K., Zeiger, L. B., Vincent, D. F., Gay, D. M., Johansson, J., Fordham, R.P., Miller, B., Clark, W., Hedley, A., Unal, E.B., Kiel, C., McGhee, E., Machesky, L. M., Nixon, C., Johnsson, A. E., Bain, M., Strathdee, D., van Hoof, S.R., Medema, J.P., Anderson, K.I., Brachmann, S.M., Stucke, V.M., Malliri, A., Drysdale, M., Turner, M., Serrano, L., Myant, K., Campbell, A. D., and Sansom, O. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine; College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © The Author(s) 2021
• First Published: First published in Nature Communications 12:56
• Publisher Policy: Reproduced under a Creative Commons license