A RAC-GEF network critical for early intestinal tumourigenesis

K. A. Pickering, K. Gilroy, J. W. Cassidy, S. K. Fey, A. K. Najumudeen, L. B. Zeiger, D. F. Vincent, D. M. Gay, J. Johansson, R. P. Fordham, B. Miller, W. Clark, A. Hedley, E. B. Unal, C. Kiel, E. McGhee, L. M. Machesky, C. Nixon, A. E. Johnsson, M. Bain, D. Strathdee, S. R. Hoof, J. P. Medema, K. I. Anderson, S. M. Brachmann, V. M. Stucke, A. Malliri, M. Drysdale, M. Turner, L. Serrano, K. Myant (), A. D. Campbell () and O. J. Sansom ()
Additional contact information
K. A. Pickering: CRUK Beatson Institute, Garscube Estate
K. Gilroy: CRUK Beatson Institute, Garscube Estate
J. W. Cassidy: University of Cambridge, Robinson Way
S. K. Fey: CRUK Beatson Institute, Garscube Estate
A. K. Najumudeen: CRUK Beatson Institute, Garscube Estate
L. B. Zeiger: CRUK Beatson Institute, Garscube Estate
D. F. Vincent: CRUK Beatson Institute, Garscube Estate
D. M. Gay: CRUK Beatson Institute, Garscube Estate
J. Johansson: CRUK Beatson Institute, Garscube Estate
R. P. Fordham: CRUK Beatson Institute, Garscube Estate
B. Miller: CRUK Beatson Institute, Garscube Estate
W. Clark: CRUK Beatson Institute, Garscube Estate
A. Hedley: CRUK Beatson Institute, Garscube Estate
E. B. Unal: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRC)
C. Kiel: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRC)
E. McGhee: CRUK Beatson Institute, Garscube Estate
L. M. Machesky: CRUK Beatson Institute, Garscube Estate
C. Nixon: CRUK Beatson Institute, Garscube Estate
A. E. Johnsson: Babraham Hall, Babraham
M. Bain: IBAHCM and School of Veterinary Medicine, 464 Bearsden Road, Bearsden
D. Strathdee: CRUK Beatson Institute, Garscube Estate
S. R. Hoof: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic Medical Center
J. P. Medema: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic Medical Center
K. I. Anderson: The Francis Crick Institute, Mill Hill Laboratory
S. M. Brachmann: Novartis Institutes for BioMedical Research
V. M. Stucke: Novartis Institutes for BioMedical Research
A. Malliri: CRUK Manchester Institute
M. Drysdale: Broad Institute
M. Turner: Babraham Hall, Babraham
L. Serrano: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRC)
K. Myant: The Institute of Genetics and Molecular Medicine
A. D. Campbell: CRUK Beatson Institute, Garscube Estate
O. J. Sansom: CRUK Beatson Institute, Garscube Estate

Nature Communications, 2021, vol. 12, issue 1, 1-14

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.

Date: 2021
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DOI: 10.1038/s41467-020-20255-4

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