Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells

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. [Display omitted] •Iron uptake and dependence are enhanced in cancer stem-like cells (CSCs)•CSCs use tumor-specific epigenetic programs to upregulate transferrin•Transferrin receptor and ferritin are necessary for tumorigenesis•Gene expression profiling reveals ferritin-dependent regulation of FoxM1 signaling Schonberg et al. show that glioblastoma cancer stem-like cells require two core iron regulators, transferrin receptor and ferritin, to propagate and form tumors and that FoxM1 is an essential downstream mediator of ferritin in these cells.