小柯机器人

间质利基协调肠肿瘤发生的旁分泌过程
2020-04-02 16:59

美国耶鲁大学医学院的Richard A. FlavellManolis Roulis以及希腊雅典国立和卡普迪斯德大学George Kollias研究组合作提出间质利基对肠肿瘤发生的旁分泌协调。相关论文发表在202041日出版的《自然》杂志上。

他们提供了体内证据证明间质位控制反式肿瘤的发生。通过使用单细胞RNA序列分析表征肠间质的异质性,他们鉴定了一群罕见的表达Ptgs2的罕见隐膜成纤维细胞,这些细胞将花生四烯酸组成性地加工成高度不稳定的前列腺素E2PGE2)。

在自发性肿瘤发生的两种不同模型中,成纤维细胞中Ptgs2的特异性敲除足以预防肿瘤起始。从机制上讲,对间质利基模型的单细胞RNA测序分析表明,成纤维细胞来源的PGE2驱动Sca-1 +储备样干细胞群体的扩增。这些表达受Hippo通路效应子Yap驱动的强大再生/致瘤程序。在体内,Yap对于Sca-1 +细胞扩增和早期肿瘤起始是必不可少的,并且在小鼠和人腺瘤中均显示出核定位。

通过类器官实验,他们确定了一种分子机制,其中PGE2通过受体Ptger4发出信号来促进Yap脱磷酸化、核易位和转录活性。Ptger4的上皮特异性敲除错误引导了干细胞的再生重编程,并阻止了突变小鼠中的Sca-1 +细胞扩增和零星的肿瘤发生,从而证明了PGE2-Ptger4肿瘤诱发干细胞的强旁分泌控制。

对患者赖来源的类器官的分析表明,PGE2-PTGER4还调节人类的干细胞功能。他们的研究表明,大肠癌的发生是由间质利基组织的,并揭示了一种机制,稀有的表达隐性Ptgs2的成纤维细胞通过可药物化的PGE2–Ptger4–Yap信号转导轴对肿瘤诱发干细胞进行旁分泌控制。

研究人员表示,肠道肿瘤的发生是一个概率过程,取决于隐窝中突变体与正常上皮干细胞之间的竞争。肠干细胞与间质细胞类型的多样化但特征不清的网络紧密相关。然而,突变干细胞的生理性间质微环境是否影响肿瘤的起始尚不清楚。

附:英文原文

Title: Paracrine orchestration of intestinal tumorigenesis by a mesenchymal niche

Author: Manolis Roulis, Aimilios Kaklamanos, Marina Schernthanner, Piotr Bielecki, Jun Zhao, Eleanna Kaffe, Laura-Sophie Frommelt, Rihao Qu, Marlene S. Knapp, Ana Henriques, Niki Chalkidi, Vasiliki Koliaraki, Jing Jiao, J. Richard Brewer, Maren Bacher, Holly N. Blackburn, Xiaoyun Zhao, Richard M. Breyer, Vassilis Aidinis, Dhanpat Jain, Bing Su, Harvey R. Herschman, Yuval Kluger, George Kollias, Richard A. Flavell

Issue&Volume: 2020-04-01

Abstract: The initiation of an intestinal tumour is a probabilistic process that depends on the competition between mutant and normal epithelial stem cells in crypts1. Intestinal stem cells are closely associated with a diverse but poorly characterized network of mesenchymal cell types2,3. However, whether the physiological mesenchymal microenvironment of mutant stem cells affects tumour initiation remains unknown. Here we provide in vivo evidence that the mesenchymal niche controls tumour initiation in trans. By characterizing the heterogeneity of the intestinal mesenchyme using single-cell RNA-sequencing analysis, we identified a population of rare pericryptal Ptgs2-expressing fibroblasts that constitutively process arachidonic acid into highly labile prostaglandin E2 (PGE2). Specific ablation of Ptgs2 in fibroblasts was sufficient to prevent tumour initiation in two different models of sporadic, autochthonous tumorigenesis. Mechanistically, single-cell RNA-sequencing analyses of a mesenchymal niche model showed that fibroblast-derived PGE2 drives the expansion οf a population of Sca-1+ reserve-like stem cells. These express a strong regenerative/tumorigenic program, driven by the Hippo pathway effector Yap. In vivo, Yap is indispensable for Sca-1+ cell expansion and early tumour initiation and displays a nuclear localization in both mouse and human adenomas. Using organoid experiments, we identified a molecular mechanism whereby PGE2 promotes Yap dephosphorylation, nuclear translocation and transcriptional activity by signalling through the receptor Ptger4. Epithelial-specific ablation of Ptger4 misdirected the regenerative reprogramming of stem cells and prevented Sca-1+ cell expansion and sporadic tumour initiation in mutant mice, thereby demonstrating the robust paracrine control of tumour-initiating stem cells by PGE2–Ptger4. Analyses of patient-derived organoids established that PGE2–PTGER4 also regulates stem-cell function in humans. Our study demonstrates that initiation of colorectal cancer is orchestrated by the mesenchymal niche and reveals a mechanism by which rare pericryptal Ptgs2-expressing fibroblasts exert paracrine control over tumour-initiating stem cells via the druggable PGE2–Ptger4–Yap signalling axis.

DOI: 10.1038/s41586-020-2166-3

Source: https://www.nature.com/articles/s41586-020-2166-3

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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