High-throughput flow cytometry screening reveals a role for junctional adhesion molecule a as a cancer stem cell maintenance factor

Justin D Lathia; Meizhang Li; Maksim Sinyuk; Alvaro G Alvarado; William A Flavahan; Kevin Stoltz; Ann Mari Rosager; James Hale; Masahiro Hitomi; Joseph Gallagher; Qiulian Wu; Jody Martin; Jason G Vidal; Ichiro Nakano; Rikke H Dahlrot; Steinbjørn Hansen; Roger E McLendon; Andrew E Sloan; Shideng Bao; Anita B Hjelmeland; Christian T Carson; Ulhas P Naik; Bjarne Kristensen; Jeremy N Rich

doi:10.1016/j.celrep.2013.11.043

High-throughput flow cytometry screening reveals a role for junctional adhesion molecule a as a cancer stem cell maintenance factor

Cell Rep. 2014 Jan 16;6(1):117-29. doi: 10.1016/j.celrep.2013.11.043. Epub 2013 Dec 27.

Authors

Justin D Lathia¹, Meizhang Li², Maksim Sinyuk³, Alvaro G Alvarado⁴, William A Flavahan⁵, Kevin Stoltz³, Ann Mari Rosager⁶, James Hale³, Masahiro Hitomi⁴, Joseph Gallagher⁷, Qiulian Wu⁷, Jody Martin⁸, Jason G Vidal⁸, Ichiro Nakano⁹, Rikke H Dahlrot¹⁰, Steinbjørn Hansen¹⁰, Roger E McLendon¹¹, Andrew E Sloan¹², Shideng Bao¹³, Anita B Hjelmeland¹³, Christian T Carson⁸, Ulhas P Naik¹⁴, Bjarne Kristensen⁶, Jeremy N Rich¹⁵

Affiliations

¹ 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.
² 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.
³ Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
⁴ 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.
⁵ 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.
⁶ Department of Pathology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense 5000, Denmark.
⁷ Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
⁸ BD Biosciences, La Jolla, CA 92037, USA.
⁹ Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
¹⁰ Department of Oncology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense 5000, Denmark.
¹¹ Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
¹² 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.
¹³ 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.
¹⁴ Department of Biology, University of Delaware, Newark, DE 19716, USA.
¹⁵ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Adhesion
Cell Adhesion Molecules / genetics
Cell Adhesion Molecules / metabolism*
Cell Line, Tumor
Flow Cytometry
Glioblastoma / metabolism
Glioblastoma / pathology
High-Throughput Screening Assays
Humans
Mice
Neoplastic Stem Cells / metabolism*
Neoplastic Stem Cells / physiology
Neural Stem Cells / metabolism
Neural Stem Cells / physiology
Receptors, Cell Surface / genetics
Receptors, Cell Surface / metabolism*
Stem Cell Niche*

Substances

Cell Adhesion Molecules
F11R protein, human
F11r protein, mouse
Receptors, Cell Surface

Abstract

Publication types

MeSH terms

Substances

Grants and funding