Rac signalling in tumourigenesis
In vitro and in vivo studies and evidence from human tumours have long implicated RAC signalling in the formation and dissemination of a range of cancers (for review see Porter et al. Small GTPases 2016). Rac1 is required for the formation of skin and lung tumours in mice and Tiam1 KO mice are resistant to skin (Malliri et al. Nature 2002) and intestinal (Malliri et al. Journal of Biological Chemistry 2006) tumours. The effect of ablating RAC activity, such as in the RAC1 and TIAM1 knockout mice, or through pharmacological inhibition, strongly indicates that targeting RAC signalling could provide effective anti-cancer therapies. RAC signalling can be disrupted in cancer by a number of mechanisms, including expression of a splice variant, RAC1b, which is highly expressed in stages 1 and 2 of human lung adenocarcinoma as well as in colorectal tumours. RAC can also be directly mutated; the P29S ‘fast cycling’ mutant is the third most common mutation in melanoma samples, and plays a role in the resistance to therapy. RAC signalling can also be disrupted by indirect mechanisms, such as overexpression of RAC GEFs, including TIAM1 (see Porter et al. Small GTPases 2016). Disruption of RAC signalling can lead to a variety of different cellular outcomes, as described below.