On the origin of colorectal cancer: Cell competition in the intestine

The epithelial monolayer of intestine is one of the fastest renewing tissues of the human body, a process that is regulated by intestinal stem cells (ISCs) residing in crypt-like structures. These ISCs continuously divide to generate differentiated cells, while simultaneously engaging in ongoing neutral competition with each other for a position within the crypt. Whenever an ISCs acquires a mutation that confers a competitive advantage, the mutant ISC gradually replaces all normal ISCs which results in permanent fixation of a mutation within the crypt and the initiation of colorectal cancer (CRC). This thesis focuses on the competition between normal and mutant ISCs, with specific emphasis on mutations that activate the Wnt pathway such as loss of Apc or activation of Ctnnb1. We reveal that Apc-mutant ISCs act as ‘supercompetitors’ that actively force normal ISCs to differentiate and leave the crypt. Moreover, we demonstrate that boosting the fitness of normal ISCs can inhibit the competitive advantage of Apc-mutant and prevent adenoma formation. These findings are particularly relevant for familial adenomatous polyposis (FAP) patients that carry germline mutations in the APC gene and are predisposed to the development of CRC. Critically, understanding the molecular basis underlying the competition between normal and mutant cells can be used to develop novel chemoprevention strategies for FAP and other heritable cancer syndromes