A RAC-GEF network critical for early intestinal tumourigenesis.
journal contributionposted on 19.08.2021, 13:14 by KA 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, KI Anderson, SM Brachmann, VM Stucke, A Malliri, M Drysdale, M Turner, L Serrano, K Myant, AD Campbell, OJ Sansom
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.
Crick (Grant ID: 10010, Grant title: STP Light Microscopy)
Adenomatous Polyposis Coli ProteinAnimalsCarcinogenesisGuanine Nucleotide Exchange FactorsHomeostasisIntestinesMice, KnockoutMutationOrgan SpecificityPhenotypeProto-Oncogene Proteins c-vavProto-Oncogene Proteins p21(ras)Signal TransductionT-Lymphoma Invasion and Metastasis-inducing Protein 1Up-RegulationWnt Signaling Pathwayrac1 GTP-Binding ProteinLMSTP FC001999