GBM CSCs require the iron regulators transferrin receptor and ferritin to drive tumorigenesis
Major finding: GBM CSCs require the iron regulators transferrin receptor and ferritin to drive tumorigenesis.
Mechanism: Gain of an epigenetic program enhances CSC iron uptake, and STAT3–FOXM1 signaling drives CSC growth.
Impact: Disrupting iron flux in CSCs is a potential therapeutic strategy for the treatment of GBM.
Glioblastoma (GBM) is the most common adult brain malignancy and, in spite of highly aggressive treatment, has a poor prognosis. The lack of treatment efficacy may be due in part to the presence of the CD133+ cancer stem-like cell (CSC) subpopulation of GBMs, which has been shown to be radioresistant and chemoresistant and can flourish in the stresses inflicted by the tumor microenvironment. These stresses are mediated in part by aberrant iron metabolism, prompting Schonberg and colleagues to investigate the role of iron regulation in the tumorigenicity of GBM CSCs. Next-generation RNA sequencing identified transferrin (TF) as the most differentially expressed gene in GBM CSCs, which secreted high levels of TF compared with non-CSCs. Epigenomic profiling revealed that TF enhancers were present in CSCs and in a cell line model of hepatocytes, suggesting that TF upregulation in CSCs is mediated by the acquisition of a liver-specific epigenetic mechanism. Consistent with these findings, iron tracing experiments showed increased unbound iron uptake in CSCs compared with non-CSCs. Expression of transferrin receptor (TfR), which mediates intracellular entry of TF-bound iron, and ferritin, which stores excess intracellular iron, was increased in a grade-dependent fashion in gliomas, in particular CSCs, and negatively correlated with patient survival. Furthermore, expression of TfR enhanced tumorsphere formation and tumor initiation, whereas knockdown of ferritin resulted in decreased CSC growth in vitro and impaired CSC tumorigenicity in vivo. Gene expression profiling revealed that this growth inhibition may be due to regulation of cell-cycle progression by ferritin and identified STAT3 as the gene most highly correlated with ferritin expression. Knockdown and rescue experiments showed that forkhead box M1 (FOXM1), a STAT3-regulated transcription factor, was critical for ferritin-mediated regulation of CSCs. Together, these results show that GBM CSC tumorigenicity is dependent on the acquisition of an epigenetic mechanism that drives iron metabolism and is potentially targetable.
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;28:441–55.
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