間質利基協調腸腫瘤發生的旁分泌過程
作者：
小柯機器人發布時間：2020/4/5 16:59:10
美國耶魯大學醫學院的Richard A. Flavell、Manolis Roulis以及希臘雅典國立和卡普迪斯德大學George Kollias研究組合作提出間質利基對腸腫瘤發生的旁分泌協調。相關論文發表在2020年4月1日出版的《自然》雜誌上。
他們提供了體內證據證明間質位控制反式腫瘤的發生。通過使用單細胞RNA序列分析表徵腸間質的異質性，他們鑑定了一群罕見的表達Ptgs2的罕見隱膜成纖維細胞，這些細胞將花生四烯酸組成性地加工成高度不穩定的前列腺素E2（PGE2）。
在自發性腫瘤發生的兩種不同模型中，成纖維細胞中Ptgs2的特異性敲除足以預防腫瘤起始。從機制上講，對間質利基模型的單細胞RNA測序分析表明，成纖維細胞來源的PGE2驅動Sca-1 +儲備樣幹細胞群體的擴增。這些表達受Hippo通路效應子Yap驅動的強大再生/致瘤程序。在體內，Yap對於Sca-1 +細胞擴增和早期腫瘤起始是必不可少的，並且在小鼠和人腺瘤中均顯示出核定位。
通過類器官實驗，他們確定了一種分子機制，其中PGE2通過受體Ptger4發出信號來促進Yap脫磷酸化、核易位和轉錄活性。Ptger4的上皮特異性敲除錯誤引導了幹細胞的再生重編程，並阻止了突變小鼠中的Sca-1 +細胞擴增和零星的腫瘤發生，從而證明了PGE2-Ptger4腫瘤誘發乾細胞的強旁分泌控制。
對患者賴來源的類器官的分析表明，PGE2-PTGER4還調節人類的幹細胞功能。他們的研究表明，大腸癌的發生是由間質利基組織的，並揭示了一種機制，稀有的表達隱性Ptgs2的成纖維細胞通過可藥物化的PGE2–Ptger4–Yap信號轉導軸對腫瘤誘發乾細胞進行旁分泌控制。
研究人員表示，腸道腫瘤的發生是一個概率過程，取決於隱窩中突變體與正常上皮幹細胞之間的競爭。腸幹細胞與間質細胞類型的多樣化但特徵不清的網絡緊密相關。然而，突變幹細胞的生理性間質微環境是否影響腫瘤的起始尚不清楚。
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