Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells

David L. Schonberg, Tyler E. Miller, Qiulian Wu, William A. Flavahan, Nupur K. Das, James S. Hale, Christopher G. Hubert, Stephen C. Mack, Awad M. Jarrar, Robert T. Karl, Ann Mari Rosager, Anne M. Nixon, Paul J. Tesar, Petra Hamerlik, Bjarne W. Kristensen, Craig Horbinski, James Connor, Paul L. Fox, Justin D. Lathia, Jeremy N. Rich

Research output: Contribution to journalArticle

84 Citations (Scopus)

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.

Original languageEnglish (US)
Article number2152
Pages (from-to)441-455
Number of pages15
JournalCancer Cell
Volume28
Issue number4
DOIs
StatePublished - Oct 12 2015

Fingerprint

Neoplastic Stem Cells
Glioblastoma
Stem Cells
Iron
Ferritins
RNA Sequence Analysis
Transferrin Receptors
Transferrin
Cell Extracts
Neoplasms
Up-Regulation
Metals
Genes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Schonberg, D. L., Miller, T. E., Wu, Q., Flavahan, W. A., Das, N. K., Hale, J. S., ... Rich, J. N. (2015). Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells. Cancer Cell, 28(4), 441-455. [2152]. https://doi.org/10.1016/j.ccell.2015.09.002
Schonberg, David L. ; Miller, Tyler E. ; Wu, Qiulian ; Flavahan, William A. ; Das, Nupur K. ; Hale, James S. ; Hubert, Christopher G. ; Mack, Stephen C. ; Jarrar, Awad M. ; Karl, Robert T. ; Rosager, Ann Mari ; Nixon, Anne M. ; Tesar, Paul J. ; Hamerlik, Petra ; Kristensen, Bjarne W. ; Horbinski, Craig ; Connor, James ; Fox, Paul L. ; Lathia, Justin D. ; Rich, Jeremy N. / Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells. In: Cancer Cell. 2015 ; Vol. 28, No. 4. pp. 441-455.
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Schonberg, DL, Miller, TE, Wu, Q, Flavahan, WA, Das, NK, Hale, JS, Hubert, CG, Mack, SC, Jarrar, AM, Karl, RT, Rosager, AM, Nixon, AM, Tesar, PJ, Hamerlik, P, Kristensen, BW, Horbinski, C, Connor, J, Fox, PL, Lathia, JD & Rich, JN 2015, 'Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells', Cancer Cell, vol. 28, no. 4, 2152, pp. 441-455. https://doi.org/10.1016/j.ccell.2015.09.002

Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells. / Schonberg, David L.; Miller, Tyler E.; Wu, Qiulian; Flavahan, William A.; Das, Nupur K.; Hale, James S.; Hubert, Christopher G.; Mack, Stephen C.; Jarrar, Awad M.; Karl, Robert T.; Rosager, Ann Mari; Nixon, Anne M.; Tesar, Paul J.; Hamerlik, Petra; Kristensen, Bjarne W.; Horbinski, Craig; Connor, James; Fox, Paul L.; Lathia, Justin D.; Rich, Jeremy N.

In: Cancer Cell, Vol. 28, No. 4, 2152, 12.10.2015, p. 441-455.

Research output: Contribution to journalArticle

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T1 - Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells

AU - Schonberg, David L.

AU - Miller, Tyler E.

AU - Wu, Qiulian

AU - Flavahan, William A.

AU - Das, Nupur K.

AU - Hale, James S.

AU - Hubert, Christopher G.

AU - Mack, Stephen C.

AU - Jarrar, Awad M.

AU - Karl, Robert T.

AU - Rosager, Ann Mari

AU - Nixon, Anne M.

AU - Tesar, Paul J.

AU - Hamerlik, Petra

AU - Kristensen, Bjarne W.

AU - Horbinski, Craig

AU - Connor, James

AU - Fox, Paul L.

AU - Lathia, Justin D.

AU - Rich, Jeremy N.

PY - 2015/10/12

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N2 - 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.

AB - 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.

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Schonberg DL, Miller TE, Wu Q, Flavahan WA, Das NK, Hale JS et al. Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells. Cancer Cell. 2015 Oct 12;28(4):441-455. 2152. https://doi.org/10.1016/j.ccell.2015.09.002