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

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 TGF beta signalling and functional analysis in ex vivo organoid cultures demonstrated that RAC1B negatively modulates TGF beta signalling and confers resistance to TGF beta-driven cell death. This work defines a novel mechanism by which early adenoma cells can overcome the cytostatic and cytotoxic effects of TGF beta signalling and characterises a new oncogenic function of RAC1B in vivo.

Automated summary

RAC1B, overexpressed in tumors, may not necessarily drive tumor invasion but accelerate tumor initiation with reduced apoptosis. It functions by attenuating TGF beta signaling and conferring resistance to TGF beta-driven cell death in early-stage adenoma cells. This study reveals a novel oncogenic function of RAC1B in vivo.