Somatic mutations in p53, which inactivate the tumour-suppressor function of p53 and often confer oncogenic gain-of-function properties, are very common in cancer 1 , 2 . Here we studied the effects of hotspot gain-of-function mutations in Trp53 (the gene that encodes p53 in mice) in mouse models of WNT-driven intestinal cancer caused by Csnk1a1 deletion 3 , 4 or Apc Min mutation 5 . Cancer in these models is known to be facilitated by loss of p53 3 , 6 . We found that mutant versions of p53 had contrasting effects in different segments of the gut: in the distal gut, mutant p53 had the expected oncogenic effect; however, in the proximal gut and in tumour organoids it had a pronounced tumour-suppressive effect. In the tumour-suppressive mode, mutant p53 eliminated dysplasia and tumorigenesis in Csnk1a1- deficient and Apc Min/+ mice, and promoted normal growth and differentiation of tumour organoids derived from these mice. In these settings, mutant p53 was more effective than wild-type p53 at inhibiting tumour formation. Mechanistically, the tumour-suppressive effects of mutant p53 were driven by disruption of the WNT pathway, through preventing the binding of TCF4 to chromatin. Notably, this tumour-suppressive effect was completely abolished by the gut microbiome. Moreover, a single metabolite derived from the gut microbiota—gallic acid—could reproduce the entire effect of the microbiome. Supplementing gut-sterilized p53-mutant mice and p53-mutant organoids with gallic acid reinstated the TCF4–chromatin interaction and the hyperactivation of WNT, thus conferring a malignant phenotype to the organoids and throughout the gut. Our study demonstrates the substantial plasticity of a cancer mutation and highlights the role of the microenvironment in determining its functional outcome. In two mouse models of intestinal cancer, mutant p53 has an oncogenic effect in the distal gut but a tumour-suppressive effect in the proximal gut, and these opposing properties are determined by the gut microbiome.

中文翻译：

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肠道微生物组将突变 p53 从抑制肿瘤转变为致癌

p53 中的体细胞突变使 p53 的肿瘤抑制功能失活并通常赋予致癌功能获得特性，在癌症中非常常见 1, 2 。在这里，我们研究了由 Csnk1a1 缺失 3、4 或 Apc Min 突变 5 引起的 WNT 驱动的肠癌小鼠模型中 Trp53（在小鼠中编码 p53 的基因）中的热点功能获得突变的影响。已知这些模型中的癌症因 p53 3, 6 的缺失而促进。我们发现 p53 的突变版本在肠道的不同部分具有对比效应：在远端肠道，突变 p53 具有预期的致癌作用；然而，在近端肠道和肿瘤类器官中，它具有明显的肿瘤抑制作用。在肿瘤抑制模式下，突变 p53 消除了 Csnk1a1 缺陷和 Apc Min/+ 小鼠的发育不良和肿瘤发生，并促进源自这些小鼠的肿瘤类器官的正常生长和分化。在这些情况下，突变型 p53 在抑制肿瘤形成方面比野生型 p53 更有效。从机制上讲，突变体 p53 的肿瘤抑制作用是由 WNT 通路的破坏驱动的，通过阻止 TCF4 与染色质的结合。值得注意的是，肠道微生物组完全消除了这种肿瘤抑制作用。此外，来自肠道微生物群的单一代谢物——没食子酸——可以再现微生物群的整个效应。用没食子酸补充肠道灭菌的 p53 突变小鼠和 p53 突变类器官恢复了 TCF4-染色质相互作用和 WNT 的过度活化，从而赋予类器官和整个肠道恶性表型。我们的研究证明了癌症突变的实质性可塑性，并强调了微环境在决定其功能结果中的作用。在两种肠癌小鼠模型中，突变的 p53 在远端肠道中具有致癌作用，但在近端肠道中具有肿瘤抑制作用，而这些相反的特性是由肠道微生物组决定的。