The regulation and stem cell origin of normal and neoplastic gastric glands are uncertain. Here, we show that Mist1 expression marks quiescent stem cells in the gastric corpus isthmus. Mist1(+) stem cells serve as a cell-of-origin for intestinal-type cancer with the combination of Kras and Apc mutation and for diffuse-type cancer with the loss of E-cadherin. Diffuse-type cancer development is dependent on inflammation mediated by Cxcl12(+) endothelial cells and Cxcr4(+) gastric innate lymphoid cells (ILCs). These cells form the perivascular gastric stem cell niche, and Wnt5a produced from ILCs activates RhoA to inhibit anoikis in the E-cadherin-depleted cells. Targeting Cxcr4, ILCs, or Wnt5a inhibits diffuse-type gastric carcinogenesis, providing targets within the neoplastic gastric stem cell niche.

Department of Biological Sciences and the Purdue Center for Cancer Research Purdue University West Lafayette IN 47907 USA

Department of Cell and Developmental Biology Institute of Molecular Genetics Academy of Sciences of the Czech Republic Prague 14220 Czech Republic

Department of Pathology and Cell Biology Columbia University College of Physicians and Surgeons New York NY 10032 USA

Department of Radiation Oncology Albert Einstein College of Medicine Bronx NY 10461 USA

Department of Tumor Pathology Gifu University Graduate School of Medicine Gifu 501 1194 Japan

Departments of Rehabilitation and Regenerative Medicine and Microbiology and Immunology Columbia University College of Physicians and Surgeons New York NY 10032 USA

Division of Clinical Pathology and Cell Biology Department of Pathology Columbia University College of Physicians and Surgeons New York NY 10032 USA

Division of Comparative Medicine Massachusetts Institute of Technology Cambridge MA 02139 USA

Division of Digestive and Liver Disease Department of Medicine Columbia University College of Physicians and Surgeons New York NY 10032 USA

Division of Digestive and Liver Disease Department of Medicine Columbia University College of Physicians and Surgeons New York NY 10032 USA; Department of General Visceral Transplantation Vascular and Thoracic Surgery Hospital of the University of Munich Munich 81377 Germany

Herbert Irving Comprehensive Cancer Center Biomedical Informatics Shared Resource and Department of Biomedical Informatics Columbia University College of Physicians and Surgeons New York NY 10032 USA

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Cell Stem Cell. 2016 Jan 7;18(1):7-9. doi: 10.1016/j.stem.2015.12.008. PubMed

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