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

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 and Nick Barker ()
Additional contact information
Si Hui Tan: A*STAR Institute of Medical Biology
Yada Swathi: A*STAR Institute of Medical Biology
Shawna Tan: A*STAR Institute of Medical Biology
Jasmine Goh: A*STAR Institute of Medical Biology
Ryo Seishima: A*STAR Institute of Medical Biology
Kazuhiro Murakami: Kanazawa University
Masanobu Oshima: Kanazawa University
Toshikatsu Tsuji: Ishikawa Prefectural Central Hospital
Phyllis Phuah: A*STAR Institute of Medical Biology
Liang Thing Tan: A*STAR Institute of Medical Biology
Esther Wong: A*STAR Institute of Medical Biology
Aliya Fatehullah: A*STAR Institute of Medical Biology
Taotao Sheng: Duke-NUS Graduate Medical School
Shamaine Wei Ting Ho: Duke-NUS Graduate Medical School
Heike I. Grabsch: Maastricht University Medical Center+
Supriya Srivastava: National University Health System
Ming Teh: National University Health System
Simon L. I. J. Denil: Skin Research Institute of Singapore
Seri Mustafah: A*STAR Singapore Immunology Network
Patrick Tan: Duke-NUS Graduate Medical School
Asim Shabbir: National University Health System
Jimmy So: National University Health System
Khay Guan Yeoh: National University of Singapore
Nick Barker: A*STAR Institute of Medical Biology

Nature, 2020, vol. 578, issue 7795, 437-443

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41586-020-1973-x

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