title: Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells.
abstract: Glioblastomas display hierarchies with self-renewing cancer stem-like cells (CSCs). RNA sequencing and enhancer mapping revealed regulatory programs unique to CSCs causing upregulation of the iron transporter transferrin, the top differentially expressed gene compared with tissue-specific progenitors. Direct interrogation of iron uptake demonstrated that CSCs potently extract iron from the microenvironment more effectively than other tumor cells. Systematic interrogation of iron flux determined that CSCs preferentially require transferrin receptor and ferritin, two core iron regulators, to propagate and form tumors in vivo. Depleting ferritin disrupted CSC mitotic progression, through the STAT3-FoxM1 regulatory axis, revealing an iron-regulated CSC pathway. Iron is a unique, primordial metal fundamental for earliest life forms, on which CSCs have an epigenetically programmed, targetable dependence.
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Schonberg
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Tyler E
authors.initials: TE
authors.lastname: Miller
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Qiulian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Flavahan
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Nupur K
authors.initials: NK
authors.lastname: Das
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Hale
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Hubert
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Mack
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Awad M
authors.initials: AM
authors.lastname: Jarrar
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Karl
authors.affiliation: Department of Clinical Pathology, Odense University Hospital, 5000 Odense, Denmark.
authors.forename: Ann Mari
authors.initials: AM
authors.lastname: Rosager
authors.affiliation: Department of Neurosurgery, Penn State College of Medicine, Hershey, PA 17033, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Nixon
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Tesar
authors.affiliation: Brain Tumor Biology Group, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
authors.forename: Petra
authors.initials: P
authors.lastname: Hamerlik
authors.affiliation: Department of Clinical Pathology, Odense University Hospital, 5000 Odense, Denmark.
authors.forename: Bjarne W
authors.initials: BW
authors.lastname: Kristensen
authors.affiliation: Division of Neuropathology, Department of Pathology, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Horbinski
authors.affiliation: Department of Neurosurgery, Penn State College of Medicine, Hershey, PA 17033, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Connor
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Fox
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lathia
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: richj@ccf.org.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D053595:Embryonic Stem Cells; D044127:Epigenesis, Genetic; D005293:Ferritins / Q000235:genetics / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D051379:Mice; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D014168:Transferrin / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; D011990:Receptors, Transferrin; D014168:Transferrin; D005293:Ferritins; D007501:Iron