Biology subjects

Slagle-Webb, B.

Publications and source records attributed to Slagle-Webb, B..

3 recordsLinked to original sources

bioRxiv2026

Iron-deficiency in the tumor microenvironment reprograms tumor-immune interactions in a sex biased manner

BackgroundGlioblastoma (GBM) is a sex-biased disease characterized by higher incidence and poorer survival in males. These sex differences are primarily driven by metabolic and immune signatures, with iron metabolism playing a major role. While iron is essential for tumor cell proliferation, it is also critical for T cell recruitment and function within the tumor microenvironment (TME). Clinical data indicates that iron deficiency impacts GBM survival in a sex-biased manner; however, the underlying mechanisms remain unexplored. MethodsWe employed a FTH1 heterozygous knockdown mouse model to induce tumor iron deficiency in GBM-bearing mice. TME dynamics were interrogated using flow cytometry and spatial transcriptomics (10X Xenium) to analyze immune infiltration, localization, and ligand-receptor signaling between GBM and immune cells. ResultsFTH1 knockdown resulted in iron deficiency in the GBM TME. Iron deficiency altered the TME dynamics in a sex biased manner. FTH1 knockdown in females caused an anti-inflammatory, cytokine deficient TME which failed to recruit CD4 and CD8 T cells. In males, FTH1 knockdown caused a proinflammatory environment by activating the innate immune response. Additionally, FTH1 knockdown increased the density of TAMs in the immediate surrounding of GBM cells in a sex biased manner. ConclusionThese results demonstrate that tumor iron plays a sex-biased role in immune infiltration and anti-tumor immunity.

cancer biology↗

bioRxiv2025

Tumor-associated macrophages protect glioblastoma cells from ferroptosis by inducing the release of ferritin-bound iron via exosomes.

Tumor-associated macrophages (TAMs) are the most abundant non-tumor cell type in glioblastoma (GBM) and act as the pivotal cell type in regulating iron metabolism in the GBM tumor microenvironment. High TAM infiltration into the TME is also associated with increased resistance to ferroptosis, an iron-dependent cell death. However, the exact mechanism by which TAMs make the cancer cells resistant to ferroptosis remains relatively unexplored. Here, we have investigated how TAMs modify iron metabolism in GBM cells to make them more resistant to ferroptotic stress. We utilized GL261 cells, a GBM cell line derived from C57BL6 mice, and syngeneic primary murine bone marrow-derived macrophages (BMDM) to study GBM-TAM interactions in vitro. We found that male macrophages exhibited higher iron uptake, greater iron storage, and a larger labile iron pool compared to female macrophages, indicating intrinsic sex biases in macrophage iron metabolism. Subsequently, we used co-culture experiments to study how macrophages regulate the iron and ferroptotic status of GL261 cells. We discovered that GL261 cells cocultured with BMDMs showed higher resistance to RSL3-induced ferroptotic stress. Mechanistically, BMDMs caused a decrease in total cellular iron in GL261 cells by inducing increased H-ferritin-bound iron release via CD63-positive exosomes; thus, limiting the amount of iron that is available for lipid peroxidation during ferroptosis. This process was moderately sex biased in favor of male macrophages. Finally, we show that this mechanism of BMDM-induced resistance to ferroptosis is independent of Hepcidin regulation and can act as a possible pathway by which GBM cells escape ferroptotic stress during proinflammatory conditions.

cancer biology↗

bioRxiv2022

Iron Inhibits Glioblastoma Cell Migration and Polarization

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. Bioinformatic analysis of CDC42 mRNA revealed a potential iron-responsive element that may contribute to the regulation of CDC42 by iron. 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.

cancer biology↗