A RAC-GEF network critical for early intestinal tumourigenesisMore about Open Access at the Crick
Authors listKA Pickering K Gilroy JW Cassidy SK Fey AK Najumudeen LB Zeiger DF Vincent DM Gay J Johansson RP Fordham B Miller W Clark A Hedley EB Unal C Kiel E McGhee LM Machesky C Nixon AE Johnsson M Bain D Strathdee SR van Hoof JP Medema Kurt Anderson SM Brachmann VM Stucke A Malliri M Drysdale M Turner L Serrano K Myant AD Campbell OJ Sansom
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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.