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RAC1B  is a tumour-related alternative splice isoform of the small GTPase  RAC1 , found overexpressed in a large number of tumour types. Building evidence suggests it promotes tumour progression but compelling in vivo evidence, demonstrating a role in driving tumour invasion, is currently lacking. In the present study, we have overexpressed  RAC1B  in a colorectal cancer mouse model with potential invasive properties. Interestingly,  RAC1B  overexpression did not trigger tumour invasion, rather it led to an acceleration of tumour initiation and reduced mouse survival. By modelling early stages of adenoma initiation we observed a reduced apoptotic rate in  RAC1B  overexpressing tumours, suggesting protection from apoptosis as a mediator of this phenotype.  RAC1B  overexpressing tumours displayed attenuated TGFβ signalling and functional analysis in ex vivo organoid cultures demonstrated that  RAC1B  negatively modulates TGFβ signalling and confers resistance to TGFβ-driven cell death. This work defines a novel mechanism by which early adenoma cells can overcome the cytostatic and cytotoxic effects of TGFβ signalling and characterises a new oncogenic function of RAC1B in vivo.

Negative regulation of TGFβ-induced apoptosis by RAC1B enhances intestinal tumourigenesis