Iron inhibits glioblastoma cell migration and polarization

Abstract

Glioblastoma is one of the deadliest malignancies facing modern oncology today. The ability of glioblastoma cells to diffusely spread into neighboring healthy brain makes complete surgical resection nearly impossible and contributes to the recurrent disease faced by most patients. Although research into the impact of iron on glioblastoma has addressed proliferation, there has been little investigation into how cellular iron impacts the ability of glioblastoma cells to migrate—a key question, especially in the context of the diffuse spread observed in these tumors. Herein, we show that increasing cellular iron content results in decreased migratory capacity of human glioblastoma cells. The decrease in migratory capacity was accompanied by a decrease in cellular polarization in the direction of movement. Expression of CDC42, a Rho GTPase that is essential for both cellular migration and establishment of polarity in the direction of cell movement, was reduced upon iron treatment. We then analyzed a single‐cell RNA‐seq dataset of human glioblastoma samples and found that cells at the tumor periphery had a gene signature that is consistent with having lower levels of cellular iron. Altogether, our results suggest that cellular iron content is impacting glioblastoma cell migratory capacity and that cells with higher iron levels exhibit reduced motility.

Analysis of anemia and iron supplementation among glioblastoma patients reveals sex-biased association between anemia and survival

“…While that study did not examine associations between iron content and survival, it did report that toe nail iron appeared to decrease the further it was collected from the date of glioblastoma diagnosis, suggesting that glioblastoma pathology and iron biology may be more closely associated than previously appreciated 52 . Recent work has also demonstrated novel anti-tumor properties of iron including promoting ferroptosis 22 , inhibiting glioblastoma cell migration 23 , and promoting anti-tumor immunity 24 . In addition to differences in the underlying etiology of anemia, the sexual dimorphism observed in trends between iron supplements and survival may, in part, be explained by differences in iron uptake.…”

“…Transcriptomic profiling has also suggested that profiles supporting iron acquisition may be associated with more aggressive phenotypes 21 . Nonetheless, recent work has also highlighted novel aspects of iron biology that may support an anti-tumor role including the promotion of cancer cell ferroptosis 22 , inhibition of glioblastoma cell migration 23 , and promotion of anti-tumor immunity 24 .…”