肠道瘤由介质形成的近管组合
Manolis Roulis1, Aimilios Kaklamanos2, Marina Schernthanner3
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. emmanouil.roulis@yale.edu.
Nature
|April 24, 2020
概括
这项研究显示,肠道中的特定纤维细胞分泌前列腺素E2 (PGE2),该前列腺素驱动储备干细胞的扩张,从而引发结肠直肠癌. 针对这种PGE2-Ptger4-Yap通路可以防止瘤发作.
科学领域:
- 胃肠病学和肝病学
- 癌症生物学
- 干细胞生物学
背景情况:
- 肠道瘤发育是一个由干细胞竞争影响的概率过程.
- 介质细胞微环境在调节肠道干细胞行为和瘤启动中的作用尚不清楚.
- 介质细胞,特别是纤维细胞,与肠道干细胞密切相关.
研究的目的:
- 调查介质微环境是否影响肠道瘤的发生.
- 确定特定的介质细胞类型和参与调节肠道干细胞和瘤启动的信号通路.
- 阐明介质控制瘤启动的分子机制.
主要方法:
- 单细胞RNA测序以表征肠中酶异质性.
- 在纤维细胞和上皮细胞中对特定基因 (Ptgs2,Ptger4) 的体内基因切除.
- 有机体实验研究细胞相互作用和信号通路.
- 对小鼠和人类腺瘤的雅普局部化分析.
主要成果:
- 鉴定出罕见的Ptgs2表达纤维细胞,产生前列腺素E2 (PGE2).
- 在小鼠模型中,纤维细胞特异性Ptgs2的切除阻止了瘤的开始.
- 纤维细胞衍生PGE2通过Hippo途径效应器Yap促进Sca-1+储备干细胞的扩张.
- 在上皮细胞上通过Ptger4发送信号的PGE2驱动Yap激活,核转位和转录活动.
- 皮质特异性Ptger4的切除阻断了瘤启动和干细胞重编程.
- PGE2- Ptger4信号调节了人类患者衍生器官的干细胞功能.
结论:
- 介质细胞通过膜信号调节结直肠癌的发生.
- 罕见的Ptgs2表达纤维细胞通过PGE2- Ptger4- Yap轴控制引发瘤的干细胞.
- 这种信号轴是预防零星结直肠癌的可用药物目标.
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