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 GSK3β. 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.

肠道干细胞 (ISC) 生态位中 WNT 激动剂和拮抗剂的微妙平衡对于维持 ISC 隔室至关重要，因为它可以适应肠道内壁的快速更新。肿瘤抑制基因APC中的突变破坏了这种平衡，这种突变存在于大约 80% 的人类结肠癌中，导致 WNT 通路不受限制地激活^1,2。先前已经确定，Apc突变细胞比野生型 ISCs 具有竞争优势³。因此，APC突变的 ISCs 经常在隐窝内胜过所有野生型干细胞，从而在组织中实现克隆固定并启动癌症形成。然而， Apc突变体 ISC的相对适应性增加是否仅涉及细胞内在特征，或者Apc突变体是否积极参与消除其野生型邻居仍未解决。在这里，我们表明Apc突变体 ISC 通过分泌 WNT 拮抗剂发挥真正的超级竞争者的作用，从而诱导邻近野生型 ISC 的分化。氯化锂阻止了Apc的扩张-突变克隆和腺瘤的形成，通过抑制 GSK3β 通过下游激活 WNT 使野生型 ISC 对 WNT 拮抗剂不敏感。我们的工作表明，提高健康细胞的适应性以限制恶变前克隆的扩增可能是限制高危个体癌症形成的有力策略。