Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells

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


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.

Publication types

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

MeSH terms

  • Animals
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology*
  • Cells, Cultured
  • Embryonic Stem Cells
  • Epigenesis, Genetic
  • Ferritins / genetics
  • Ferritins / metabolism*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Profiling
  • Glioblastoma / genetics
  • Glioblastoma / metabolism
  • Glioblastoma / pathology*
  • Humans
  • Iron / metabolism*
  • Mice
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Receptors, Transferrin / genetics
  • Receptors, Transferrin / metabolism*
  • Sequence Analysis, RNA
  • Signal Transduction
  • Transferrin / metabolism


  • Forkhead Transcription Factors
  • Receptors, Transferrin
  • Transferrin
  • Ferritins
  • Iron

Associated data

  • GEO/GSE72204