@article{7325777687f745158f35d701a859953f,
title = "A RAC-GEF network critical for early intestinal tumourigenesis",
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.",
author = "Pickering, {K. A.} and K. Gilroy and Cassidy, {J. W.} and Fey, {S. K.} and Najumudeen, {A. K.} and Zeiger, {L. B.} and Vincent, {D. F.} and Gay, {D. M.} and J. Johansson and Fordham, {R. P.} and B. Miller and W. Clark and A. Hedley and Unal, {E. B.} and C. Kiel and E. McGhee and Machesky, {L. M.} and C. Nixon and Johnsson, {A. E.} and M. Bain and D. Strathdee and {van Hoof}, {S. R.} and Medema, {J. P.} and Anderson, {K. I.} and Brachmann, {S. M.} and Stucke, {V. M.} and A. Malliri and M. Drysdale and M. Turner and L. Serrano and K. Myant and Campbell, {A. D.} and Sansom, {O. J.}",
note = "Funding 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). Thanks to Glasgow University Veterinary Diagnostic services for blood serum analysis. Thanks to histology, microscopy and the BSU for enabling this work to be carried out. Thanks to Victor Tybulewicz for Rac1 flox mice, and Heidi Welch for Raichu-Rac1 report mice. We thank Heidi Welch for critical review of the manuscript. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
day = "1",
doi = "https://doi.org/10.1038/s41467-020-20255-4",
language = "English",
volume = "12",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}