Iron promotes isocitrate dehydrogenase mutant glioma cell motility.

Enriched iron metabolic features such as high transferrin receptor (TfR) expression and high iron content are commonly observed in aggressive gliomas and can be associated with poor clinical responses. However, the underlying question of how iron contributes to tumor aggression remains elusive. Gliomas harboring isocitrate dehydrogenase (IDH) mutations account for a high percentage (>70 %) of recurrent tumors and cells with an acquired IDH mutation have been reported to have increased motility and invasion. This study aims to investigate how an acquired IDH mutation modulates iron metabolism and the implication(s) of iron on tumor cell growth. IDH mutant cells (U87^R132H) grow significantly faster which is accompanied with increased TfR expression and iron uptake in vitro compared to wild-type U87 cells. This phenotype is retained in vivo. Biomechanically, U87^R132H cells are significantly less stiff and supplementation with ferrous ammonium sulfate (Fe²⁺) augments membrane fluidity to drive U87^R132H cells into a super motile state. These findings provide insight into how an acquired IDH mutation may be able to modulate iron metabolism, allowing iron to serve as a biomechanical driver of tumor progression.