The tumour suppressor APC is the most commonly mutated gene in colorectal cancer. Loss of Apc in intestinal stem cells drives the formation of adenomas in mice via increased WNT signalling¹, but reduced secretion of WNT ligands increases the ability of Apc-mutant intestinal stem cells to colonize a crypt (known as fixation)². Here we investigated how Apc-mutant cells gain a clonal advantage over wild-type counterparts to achieve fixation. We found that Apc-mutant cells are enriched for transcripts that encode several secreted WNT antagonists, with Notum being the most highly expressed. Conditioned medium from Apc-mutant cells suppressed the growth of wild-type organoids in a NOTUM-dependent manner. Furthermore, NOTUM-secreting Apc-mutant clones actively inhibited the proliferation of surrounding wild-type crypt cells and drove their differentiation, thereby outcompeting crypt cells from the niche. Genetic or pharmacological inhibition of NOTUM abrogated the ability of Apc-mutant cells to expand and form intestinal adenomas. We identify NOTUM as a key mediator during the early stages of mutation fixation that can be targeted to restore wild-type cell competitiveness and provide preventative strategies for people at a high risk of developing colorectal cancer.

抑癌基因APC是结直肠癌中最常见的突变基因。肠道干细胞中Apc的缺失会通过增加 WNT 信号传导来驱动小鼠腺瘤的形成^{1 ，但 WNT 配体分泌的减少会增加}Apc突变型肠道干细胞定殖于隐窝（称为固定）的能力²。在这里，我们研究了Apc突变细胞如何获得相对于野生型对应物的克隆优势来实现固定。我们发现Apc突变细胞富含编码几种分泌性 WNT 拮抗剂的转录物，其中Notum表达最高。Apc突变细胞的条件培养基以 NOTUM 依赖性方式抑制野生型类器官的生长。此外，分泌NOTUM的Apc突变克隆积极抑制周围野生型隐窝细胞的增殖并驱动它们的分化，从而在竞争中胜过小生境中的隐窝细胞。NOTUM 的遗传或药理学抑制消除了Apc突变细胞扩张和形成肠腺瘤的能力。我们将 NOTUM 确定为突变固定早期阶段的关键介质，可以有针对性地恢复野生型细胞的竞争力，并为结直肠癌高风险人群提供预防策略。