Apc-mutant cells act as supercompetitors in intestinal tumour initiation

A delicate equilibrium of WNT agonists and antagonists in the intestinal stem cell (ISC) niche is critical to maintaining the ISC compartment, as it accommodates the rapid renewal of the gut lining. Disruption of this balance by mutations in the tumour suppressor gene APC, which are found in approximately 80% of all human colon cancers, leads to unrestrained activation of the WNT pathway(1,2). It has previously been established that Apc-mutant cells have a competitive advantage over wild-type ISCs3. Consequently, Apc-mutant ISCs frequently outcompete all wild-type stem cells within a crypt, thereby reaching clonal fixation in the tissue and initiating cancer formation. However, whether the increased relative fitness of Apc-mutant ISCs involves only cell-intrinsic features or whether Apc mutants are actively involved in the elimination of their wild-type neighbours remains unresolved. Here we show that Apc-mutant ISCs function as bona fide supercompetitors by secreting WNT antagonists, thereby inducing differentiation of neighbouring wild-type ISCs. Lithium chloride prevented the expansion of Apc-mutant clones and the formation of adenomas by rendering wild-type ISCs insensitive to WNT antagonists through downstream activation of WNT by inhibition of GSK3 beta. Our work suggests that boosting the fitness of healthy cells to limit the expansion of pre-malignant clones may be a powerful strategy to limit the formation of cancers in high-risk individuals.

Automated summary

In the ISC niche, the delicate balance of WNT agonists and antagonists is crucial for maintaining the ISC compartment and preventing unrestrained activation of the WNT pathway. Apc-mutant ISCs function as supercompetitors by secreting WNT antagonists to induce differentiation of neighboring wild-type ISCs. Lithium chloride prevents the expansion of Apc-mutant clones and adenoma formation by rendering wild-type ISCs insensitive to WNT antagonists through downstream activation of WNT by inhibiting GSK3 beta. Boosting the fitness of healthy cells may be a powerful strategy to limit the formation of cancers in high-risk individuals.