小柯机器人

以色列希伯来大学-哈达萨医学院Yinon Ben-Neriah研究组近日取得一项新成果。他们发现肠道微生物组可将突变型p53从抑制肿瘤转变为致癌。相关论文发表在2020年7月29日出版的《自然》杂志上。

他们研究了由Csnk1a1缺失或ApcMin突变引起的WNT驱动的肠癌小鼠模型中Trp53（在小鼠中编码p53的基因）中的热点功能突变的影响。已知这些模型中的癌症可通过p53的丢失而促进。他们发现p53突变体在肠道的不同部位具有对比作用：在远端肠道中，p53突变体具有预期的致癌作用；然而，在近端肠道和肿瘤类器官中，它具有显著的肿瘤抑制作用。

在肿瘤抑制模型下，突变体p53消除了Csnk1a1缺陷和ApcMin / +小鼠的不典型增生和肿瘤发生，并促进了这些小鼠来源的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，突变型p53的肿瘤抑制作用是通过阻止WNT途径（通过阻止TCF4与染色质的结合）来驱动的。

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，源自肠道菌群的单一代谢物-没食子酸可以重现微生物组的全部作用。给予肠道无菌菌的p53突变小鼠和p53突变类器官没食子酸，可恢复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以恶性表型。他们的研究证明了癌症突变的可塑性，并强调了微环境在决定其功能预后方面的作用。

此外，源自肠道菌群的单一代谢物-没食子酸可以重现微生物组的全部作用。用没食子酸补充经肠道灭菌的p53突变小鼠和p53突变类器官，可恢复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以恶性表型。他们的研究表明癌症突变的持续可塑性，并强调微环境在决定其功能的作用。

据介绍，p53中的体细胞突变会导致其丧失肿瘤抑制功能，并通常赋予癌症功能获得特性，在癌症中非常常见。

附：英文原文

Title: The gut microbiome switches mutant p53 from tumour-suppressive to oncogenic

Author: Eliran Kadosh, Irit Snir-Alkalay, Avanthika Venkatachalam, Shahaf May, Audrey Lasry, Ela Elyada, Adar Zinger, Maya Shaham, Gitit Vaalani, Marco Mernberger, Thorsten Stiewe, Eli Pikarsky, Moshe Oren, Yinon Ben-Neriah

Issue&Volume: 2020-07-29

Abstract: Somatic mutations in p53, which inactivate the tumour-suppressor function of p53 and often confer oncogenic gain-of-function properties, are very common in cancer1,2. 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 deletion3,4 or ApcMin mutation5. Cancer in these models is known to be facilitated by loss of p533,6. 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 ApcMin/+ 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.

DOI: 10.1038/s41586-020-2541-0

Source: https://www.nature.com/articles/s41586-020-2541-0

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