Taking flight Wnt-driven stem cell competition in colorectal cancer initiation

The intestinal epithelium undergoes constant renewal driven by intestinal stem cells (ISCs), located within intestinal crypts, which generate all specialized cell types of the gut. To maintain tissue homeostasis, ISCs continuously divide while competing with neighbouring ISCs for their position within the crypt. When an ISC acquires an oncogenic mutation that confers a competitive advantage, it can progressively replace neighbouring wild-type ISCs, resulting in clonal fixation within the crypt and potentially initiating colorectal cancer (CRC). Loss of APC is among the earliest and most common genetic events in CRC, leading to constitutive Wnt pathway activation and giving a competitive advantage to mutant ISCs.
This thesis investigates the behaviour of Apc-mutant ISCs and explores three strategies to counteract their competitive advantage: enhancing wild-type ISC fitness, targeting factors secreted by mutant cells and exploiting vulnerabilities that emerge following Apc loss. We demonstrate that Apc-mutant ISCs act as ‘supercompetitors’, secreting Wnt antagonists that drive differentiation of neighbouring wild-type ISCs. Enhancing Wnt signalling in wild-type ISCs prevents adenoma formation, while specific targeting of Wnt antagonist NOTUM reduces mutant clone expansion but is insufficient to prevent tumour formation. We further identify functional and metabolic heterogeneity among distinct Apc mutations and uncover cellular stress responses as a vulnerability of Apc-mutant cells. Targeting this vulnerability suppresses CRC development.
These findings are particularly relevant for familial adenomatous polyposis (FAP), where patients carry germline APC mutations and are predisposed to CRC. Moreover, they provide a framework for preventative strategies applicable to other hereditary intestinal cancer syndromes, including Lynch syndrome.