创作:Lexi 审核:Lexi 2020年03月01日
  • 分析小鼠胃肠道LGR5+幽门干细胞转录组,发现该细胞群体高表达膜水通道蛋白AQP5;
  • 谱系示踪实验表明LGR5+细胞具有自我更新能力和多能性,表达GIF等胃谱系标记物,是有效富集小鼠幽门干细胞的标记物;
  • AQP5也可作为从人胃上皮细胞中分离富集内源性干细胞的标记物;
  • 小鼠活体实验表明幽门干细胞是WNT驱动的侵入性胃癌来源,且离体AQP5+肿瘤细胞具有干细胞潜能;
  • AQP5常在原发型肠道/弥漫型胃癌及其转移灶中表达。
Nature [IF:42.778]

AQP5 enriches for stem cells and cancer origins in the distal stomach



2020-02-05, Article

Abstract & Authors:展开

LGR5 marks resident adult epithelial stem cells at the gland base in the mouse pyloric stomach1, but the identity of the equivalent human stem cell population remains unknown owing to a lack of surface markers that facilitate its prospective isolation and validation. In mouse models of intestinal cancer, LGR5+ intestinal stem cells are major sources of cancer following hyperactivation of the WNT pathway2. However, the contribution of pyloric LGR5+ stem cells to gastric cancer following dysregulation of the WNT pathway—a frequent event in gastric cancer in humans3—is unknown. Here we use comparative profiling of LGR5+ stem cell populations along the mouse gastrointestinal tract to identify, and then functionally validate, the membrane protein AQP5 as a marker that enriches for mouse and human adult pyloric stem cells. We show that stem cells within the AQP5+ compartment are a source of WNT-driven, invasive gastric cancer in vivo, using newly generated Aqp5-creERT2 mouse models. Additionally, tumour-resident AQP5+ cells can selectively initiate organoid growth in vitro, which indicates that this population contains potential cancer stem cells. In humans, AQP5 is frequently expressed in primary intestinal and diffuse subtypes of gastric cancer (and in metastases of these subtypes), and often displays altered cellular localization compared with healthy tissue. These newly identified markers and mouse models will be an invaluable resource for deciphering the early formation of gastric cancer, and for isolating and characterizing human-stomach stem cells as a prerequisite for harnessing the regenerative-medicine potential of these cells in the clinic.

First Authors:
Si Hui Tan,Yada Swathi

Correspondence Authors:
Nick Barker

All Authors:
Si Hui Tan,Yada Swathi,Shawna Tan,Jasmine Goh,Ryo Seishima,Kazuhiro Murakami,Masanobu Oshima,Toshikatsu Tsuji,Phyllis Phuah,Liang Thing Tan,Esther Wong,Aliya Fatehullah,Taotao Sheng,Shamaine Wei Ting Ho,Heike I Grabsch,Supriya Srivastava,Ming Teh,Simon L I J Denil,Seri Mustafah,Patrick Tan,Asim Shabbir,Jimmy So,Khay Guan Yeoh,Nick Barker