Uptake of H-ferritin by Glioblastoma stem cells and its impact on their invasion capacity

PurposeIron acquisition is key to maintaining cell survival and function. Cancer cells in general are considered to have an insatiable iron need. Iron delivery via the transferrin/transferrin receptor pathway has been the canonical iron uptake mechanism. Recently, however, our laboratory and others have explored the ability of ferritin, particularly the H-subunit, to deliver iron to a variety of cell types. Here, we investigate whether Glioblastoma (GBM) initiating cells (GICs), a small population of stem-like cells, are known for their iron addiction and invasive nature acquire exogenous ferritin, as a source of iron. We further assess the functional impact of ferritin uptake on the invasion capacity of the GICs.MethodsTo establish that H-ferritin can bind to human GBM, tissue-binding assays were performed on samples collected at the time of surgery. To interrogate the functional consequences of H-ferritin uptake, we utilized two patient-derived GIC lines. We further describe H-ferritin's impact on GIC invasion capacity using a 3D invasion assay.ResultsH-ferritin bound to human GBM tissue at the amount of binding was influenced by sex. GIC lines showed uptake of H-ferritin protein via transferrin receptor. FTH1 uptake correlated with a significant decrease in the invasion capacity of the cells. H-ferritin uptake was associated with a significant decrease in the invasion-related protein Rap1A.ConclusionThese findings indicate that extracellular H-ferritin participates in iron acquisition to GBMs and patient-derived GICs. The functional significance of the increased iron delivery by H-ferritin is a decreased invasion capacity of GICs potentially via reduction of Rap1A protein levels.

Automated summary

Iron acquisition is crucial for cell survival and function. While iron is typically acquired via the transferrin/transferrin receptor pathway, recent research has shown that ferritin, particularly the H-subunit, can also deliver iron to various cell types. This study investigates whether Glioblastoma initiating cells (GICs) acquire exogenous ferritin and the impact of ferritin uptake on their invasion capacity. The results demonstrate that H-ferritin binds to human GBM tissue and its uptake decreases the invasion capacity of GICs potentially through reduction of Rap1A protein levels.