title: Mist1 Expressing Gastric Stem Cells Maintain the Normal and Neoplastic Gastric Epithelium and Are Supported by a Perivascular Stem Cell Niche.
abstract: 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.
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Yoku
authors.initials: Y
authors.lastname: Hayakawa
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ariyama
authors.affiliation: Department of Cell and Developmental Biology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague 14220, Czech Republic.
authors.forename: Jitka
authors.initials: J
authors.lastname: Stancikova
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Sakitani
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Asfaha
authors.affiliation: 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.
authors.forename: Bernhard W
authors.initials: BW
authors.lastname: Renz
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Zinaida A
authors.initials: ZA
authors.lastname: Dubeykovskaya
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Wataru
authors.initials: W
authors.lastname: Shibata
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Hongshan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Christoph B
authors.initials: CB
authors.lastname: Westphalen
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Chen
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takemoto
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Woosook
authors.initials: W
authors.lastname: Kim
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Shradha S
authors.initials: SS
authors.lastname: Khurana
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Yagnesh
authors.initials: Y
authors.lastname: Tailor
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Karan
authors.initials: K
authors.lastname: Nagar
authors.affiliation: Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tomita
authors.affiliation: Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
authors.affiliation: Division of Clinical Pathology and Cell Biology, Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Antonia R
authors.initials: AR
authors.lastname: Sepulveda
authors.affiliation: Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Wanda
authors.initials: W
authors.lastname: Setlik
authors.affiliation: Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Gershon
authors.affiliation: Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Subhrajit
authors.initials: S
authors.lastname: Saha
authors.affiliation: Departments of Rehabilitation and Regenerative Medicine and Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Ding
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Zeli
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.affiliation: 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.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Friedman
authors.affiliation: Department of Biological Sciences and the Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Konieczny
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Worthley
authors.affiliation: Department of Cell and Developmental Biology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague 14220, Czech Republic.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Korinek
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address: tcw21@columbia.edu.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
mesh_terms: D000818:Animals; D023102:Anoikis; D000970:Antineoplastic Agents / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D015820:Cadherins / Q000378:metabolism; D002450:Cell Communication; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016922:Cellular Senescence; D054377:Chemokine CXCL12 / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction; D055153:Stem Cell Niche; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D059016:Tumor Microenvironment; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D015820:Cadherins; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; C559697:BHLHA15 protein, human; C491312:Bhlha15 protein, mouse; C514936:CXCR4 protein, mouse; C515256:Cxcl12 protein, mouse; C438615:Wnt5a protein, mouse; C526380:RhoA protein, mouse