Mutation of the APC gene is a common occurrence in colorectal cancer. Sansom and colleagues now report that following Apc loss, RAC1 activity drives proliferation of LGR5-positive intestinal stem cells (ISCs) and tumorigenesis through ROS production and NF-κB signalling (Cell Stem Cell 12, 761–773; 2013).

In line with previous reports, the authors showed that Apc loss led to the Myc-dependent upregulation of Rac guanine exchange nucleotide factors (GEFs), Rac1b and subsequent activation of Rac1. Deletion of Rac1 in the mouse intestine decreased the hyperproliferation of intestinal crypt progenitors, the expansion of the LGR5-marked ISC population and the upregulation of ISC gene signatures observed in the context of Apc deficiency. Rac1 is known to promote ROS production, and the authors observed that increased ROS levels were required for LGR5-positive cell expansion following Apc loss and RAC1 activation. The NF-κB pathway, which has been previously linked to ISC expansion, was also found to promote the hyperproliferation of LGR5-marked cells downstream of Rac1. Deletion of Rac1 was further shown to prevent mouse intestinal adenoma formation following Apc loss in the LGR5-positive cell population, and ROS reduction also extended the tumour-free lifespan of these Apc-deficient mice. When induced after tumours were allowed to form, Rac1 deletion reduced the LGR5-positive tumour cell population of Apc-mutant mice.

These findings underscore the importance of Rac1 activity in intestinal tumorigenesis.