title: High-throughput flow cytometry screening reveals a role for junctional adhesion molecule a as a cancer stem cell maintenance factor.
abstract: Stem cells reside in niches that regulate the balance between self-renewal and differentiation. The identity of a stem cell is linked with the ability to interact with its niche through adhesion mechanisms. To identify targets that disrupt cancer stem cell (CSC) adhesion, we performed a flow cytometry screen on patient-derived glioblastoma (GBM) cells and identified junctional adhesion molecule A (JAM-A) as a CSC adhesion mechanism essential for self-renewal and tumor growth. JAM-A was dispensable for normal neural stem/progenitor cell (NPC) function, and JAM-A expression was reduced in normal brain versus GBM. Targeting JAM-A compromised the self-renewal of CSCs. JAM-A expression negatively correlated to GBM patient prognosis. Our results demonstrate that GBM-targeting strategies can be identified through screening adhesion receptors and JAM-A represents a mechanism for niche-driven CSC maintenance.
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA; Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA. Electronic address: lathiaj@ccf.org.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lathia
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA; Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA; Laboratory of Biochemistry and Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China.
authors.forename: Meizhang
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
authors.forename: Maksim
authors.initials: M
authors.lastname: Sinyuk
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA.
authors.forename: Alvaro G
authors.initials: AG
authors.lastname: Alvarado
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Flavahan
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Stoltz
authors.affiliation: Department of Pathology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense 5000, Denmark.
authors.forename: Ann Mari
authors.initials: AM
authors.lastname: Rosager
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
authors.forename: James
authors.initials: J
authors.lastname: Hale
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hitomi
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Gallagher
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
authors.forename: Qiulian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: BD Biosciences, La Jolla, CA 92037, USA.
authors.forename: Jody
authors.initials: J
authors.lastname: Martin
authors.affiliation: BD Biosciences, La Jolla, CA 92037, USA.
authors.forename: Jason G
authors.initials: JG
authors.lastname: Vidal
authors.affiliation: Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
authors.affiliation: Department of Oncology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense 5000, Denmark.
authors.forename: Rikke H
authors.initials: RH
authors.lastname: Dahlrot
authors.affiliation: Department of Oncology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense 5000, Denmark.
authors.forename: Steinbjørn
authors.initials: S
authors.lastname: Hansen
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.affiliation: Case Comprehensive Cancer Center, Cleveland, OH 44106, USA; Seidman Cancer Center, University Hospital-Case Medical Center, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Departments of Neurological Surgery, Pathology, and Translational Neuroscience, University Hospital-Case Medical Center, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Sloan
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA.
authors.forename: Shideng
authors.initials: S
authors.lastname: Bao
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA.
authors.forename: Anita B
authors.initials: AB
authors.lastname: Hjelmeland
authors.affiliation: BD Biosciences, La Jolla, CA 92037, USA.
authors.forename: Christian T
authors.initials: CT
authors.lastname: Carson
authors.affiliation: Department of Biology, University of Delaware, Newark, DE 19716, USA.
authors.forename: Ulhas P
authors.initials: UP
authors.lastname: Naik
authors.affiliation: Department of Pathology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense 5000, Denmark.
authors.forename: Bjarne
authors.initials: B
authors.lastname: Kristensen
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA; Case Comprehensive Cancer Center, Cleveland, OH 44106, USA. Electronic address: drjeremyrich@gmail.com.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000502:physiology; D058953:Neural Stem Cells / Q000378:metabolism / Q000502:physiology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D055153:Stem Cell Niche
chemical_list: D015815:Cell Adhesion Molecules; C407243:F11R protein, human; C498686:F11r protein, mouse; D011956:Receptors, Cell Surface