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Cancer Cell. 2015 Oct 12;28(4):441-455. doi: 10.1016/j.ccell.2015.09.002.

Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells.

Author information

1
Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
2
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
3
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
4
Department of Clinical Pathology, Odense University Hospital, 5000 Odense, Denmark.
5
Department of Neurosurgery, Penn State College of Medicine, Hershey, PA 17033, USA.
6
Brain Tumor Biology Group, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
7
Division of Neuropathology, Department of Pathology, University of Kentucky, Lexington, KY 40536, USA.
8
Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: richj@ccf.org.

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.

PMID:
26461092
PMCID:
PMC4646058
DOI:
10.1016/j.ccell.2015.09.002
[Indexed for MEDLINE]
Free PMC Article

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