CBIO-06. CELL INTRINSIC HFE DRIVES SEX-SPECIFIC GLIOBLASTOMA GROWTH Free

Iron is an essential element required for a number of cellular processes and can contribute to malignant transformation and tumor expansion. In glioblastoma (GBM), tumor cells have been shown to modulate expression of iron-associated proteins to enhance iron uptake from the surrounding microenvironment, driving proliferation and tumor growth. The homeostatic iron regulatory (HFE) gene encodes a transmembrane glycoprotein that aids in iron homeostasis by modulating iron uptake and release. HFE is upregulated in GBM tumors compared to non-tumor brain and expression of HFE increases with tumor grade. Furthermore, HFE mRNA expression is associated with significantly reduced survival specifically in female patients with GBM. However, it is unclear how HFE impacts sex-specific GBM growth. To interrogate the underlying mechanism of HFE-mediated sex differences, we employed genetic loss and gain of function approaches using syngeneic mouse glioma models. We observed significant alterations in the expression of several iron-associated genes with Hfe knockdown or overexpression, suggesting global disruption of iron homeostasis. We found that knockdown of Hfe decreased cell number and increased apoptosis in vitro and led to a significant impairment of tumor growth in vivo, with a more pronounced effect seen in female mice. Conversely, overexpression of Hfe increased cell number and significantly decreased survival only in female animals. These findings support the hypothesis that Hfe is a critical regulator of cellular iron status and contributes to tumor aggression in a sex-dependent manner. These data also suggest an unexplored link between cell intrinsic iron signaling and sex-specific microenvironmental and immune responses, which is the focus of ongoing studies.