A RAC-GEF network critical for early intestinal tumourigenesis

Nat Commun. 2021 Jan 4;12(1):56. doi: 10.1038/s41467-020-20255-4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli Protein / metabolism
  • Animals
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism*
  • Carcinogenesis / pathology*
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Homeostasis
  • Intestines / pathology*
  • Intestines / ultrastructure
  • Mice
  • Mice, Knockout
  • Mutation / genetics
  • Organ Specificity
  • Phenotype
  • Proto-Oncogene Proteins c-vav / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Signal Transduction*
  • T-Lymphoma Invasion and Metastasis-inducing Protein 1 / metabolism
  • Up-Regulation
  • Wnt Signaling Pathway
  • rac1 GTP-Binding Protein / metabolism*


  • Adenomatous Polyposis Coli Protein
  • Guanine Nucleotide Exchange Factors
  • Proto-Oncogene Proteins c-vav
  • T-Lymphoma Invasion and Metastasis-inducing Protein 1
  • Vav2 protein, mouse
  • Vav3 protein, mouse
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • rac1 GTP-Binding Protein