title: A CDC20-APC/SOX2 Signaling Axis Regulates Human Glioblastoma Stem-like Cells.
abstract: Glioblastoma harbors a dynamic subpopulation of glioblastoma stem-like cells (GSCs) that can propagate tumors in vivo and is resistant to standard chemoradiation. Identification of the cell-intrinsic mechanisms governing this clinically important cell state may lead to the discovery of therapeutic strategies for this challenging malignancy. Here, we demonstrate that the mitotic E3 ubiquitin ligase CDC20-anaphase-promoting complex (CDC20-APC) drives invasiveness and self-renewal in patient tumor-derived GSCs. Moreover, CDC20 knockdown inhibited and CDC20 overexpression increased the ability of human GSCs to generate brain tumors in an orthotopic xenograft model in vivo. CDC20-APC control of GSC invasion and self-renewal operates through pluripotency-related transcription factor SOX2. Our results identify a CDC20-APC/SOX2 signaling axis that controls key biological properties of GSCs, with implications for CDC20-APC-targeted strategies in the treatment of glioblastoma.
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Diane D
authors.initials: DD
authors.lastname: Mao
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Amit D
authors.initials: AD
authors.lastname: Gujar
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; Program in Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Tatenda
authors.initials: T
authors.lastname: Mahlokozera
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Ishita
authors.initials: I
authors.lastname: Chen
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Division of Biostatistics, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jingqin
authors.initials: J
authors.lastname: Luo
authors.affiliation: Program in Molecular Cell Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Brost
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Thompson
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Turski
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Leuthardt
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Dunn
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Chicoine
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Rich
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Dowling
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Zipfel
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Ralph G
authors.initials: RG
authors.lastname: Dacey
authors.affiliation: Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Achilefu
authors.affiliation: Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Tran
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yano
authors.affiliation: Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: kima@wudosis.wustl.edu.
authors.forename: Albert H
authors.initials: AH
authors.lastname: Kim
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D064199:Cdc20 Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; D064199:Cdc20 Proteins; D055748:SOXB1 Transcription Factors; C577488:CDC20 protein, human; D064173:Anaphase-Promoting Complex-Cyclosome