Cell & Developmental Biology, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, Scotland.
National Phenotypic Screening Centre, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, Scotland.
Cell Death Dis. 2018 Feb 15;9(3):255. doi: 10.1038/s41419-017-0199-9.
More than 90% of colorectal cancers carry mutations in Apc that drive tumourigenesis. A 'just-right' signalling model proposes that Apc mutations stimulate optimal, but not excessive Wnt signalling, resulting in a growth advantage of Apc mutant over wild-type cells. Reversal of this growth advantage constitutes a potential therapeutic approach. We utilised intestinal organoids to compare the growth of Apc mutant and wild-type cells. Organoids derived from Apc mice recapitulate stages of intestinal polyposis in culture. They eventually form spherical cysts that reflect the competitive growth advantage of cells that have undergone loss of heterozygosity (LOH). We discovered that this emergence of cysts was inhibited by Chiron99021 and Valproic acid, which potentiates Wnt signalling. Chiron99021 and Valproic acid restrict the growth advantage of Apc mutant cells while stimulating that of wild-type cells, suggesting that excessive Wnt signalling reduces the relative fitness of Apc mutant cells. As a proof of concept, we demonstrated that Chiron99021-treated Apc mutant organoids were rendered susceptible to TSA-induced apoptosis, while wild-type cells were protected.
超过 90%的结直肠癌携带驱动肿瘤发生的 APC 突变。一个“恰到好处”的信号模型提出，APC 突变刺激最佳但不过度的 Wnt 信号，导致 APC 突变体相对于野生型细胞具有生长优势。逆转这种生长优势构成了一种潜在的治疗方法。我们利用肠类器官来比较 APC 突变体和野生型细胞的生长。源自 Apc 小鼠的类器官在培养中再现了肠息肉形成的各个阶段。它们最终形成球形囊肿，反映了经历杂合性丢失 (LOH) 的细胞的竞争生长优势。我们发现，Chiron99021 和丙戊酸抑制了囊肿的出现，丙戊酸增强了 Wnt 信号。Chiron99021 和丙戊酸限制了 APC 突变体细胞的生长优势，同时刺激了野生型细胞的生长，表明过度的 Wnt 信号降低了 APC 突变体细胞的相对适应性。作为概念验证，我们证明了用 Chiron99021 处理的 APC 突变体类器官易受 TSA 诱导的细胞凋亡，而野生型细胞则受到保护。
