VilCreER APCfl/fl vs VilCreER APCfl/fl, Vav2-/-, Vav3-/-, Tiam1-/-. RAC-GEF function as a critical factor in intestinal tumourigenesis

RAC1 GTPase is important for cell transformation. We showed deletion of RAC1 from the intestine suppresses phenotypes associated with acute loss of the Adenomatous Polyposis Coli tumour suppressor. However, intestinal RAC1 deficiency also profoundly affected homeostasis, disrupting barrier function. We reasoned that interfering with specific Rac-GEFs may prove less harmful. We profiled APC-loss dependent GEF expression and found marked deregulation of Vav3 and Tiam1. TIAM1 deficiency supressed the proliferation caused by APC loss but had no effect on the stem cell phenotype or tumourigenesis and VAV3 deficiency affected neither of these. Loss of VAV3 or TIAM1 resulted in compensatory upregulation of Vav2. Mice with multiple GEF deficiency (VAV2–/– VAV3–/–, TIAM1–/–) showed normal intestinal homeostasis, but importantly hyperproliferation, increased stem cell number and tumourigenesis caused by APC loss was suppressed. Mechanistically, we observed a spatial reduction in RAC1 activity, most notably at cell junctions. Together, we show it would be beneficial to target GEFs to suppress RAC1 activity, thus separating roles in actin homeostasis from those in proliferation and stemness.