Metabolic Landscape Changes and Ferroptosis in Recurrent Glioma

Introduction: Low-grade gliomas (LGGs) represent 10-20% of all primary central nervous system tumors. While mutations in isocitrate dehydrogenase-1 (IDH1) are a defining feature of LGGs, recurrence is frequent and often leads to aggressive high-grade glioma. Approximately 70% of LGG patients progress to high-grade glioma within a decade. Recent studies suggest that glioblastomas (GBMs) can be sensitized to ferroptosis, an iron-dependent form of cell death, yet this phenomenon remains unexplored in LGGs. Our ongoing research aims to investigate the role of ferroptosis in a novel cellular model of IDH1-mutated glioma. We are utilizing murine glioma cell lines expressing either IDH1WT or IDH1R132H (IDH1 mutant), which are serially transplanted into immune-competent mice to develop C266-6 (wildtype, IDH1WT) and C266-2 (mutant, IDH1R132H) cell lines.

Methods: Current studies involve assessing ferroptosis-related activity and RNA expression profiles under various basal and treatment conditions.

Results: Preliminary findings indicate that IDH1 mutant cell lines exhibit resistance to ferroptosis induction compared to IDH1 WT glioma cells. Ferroptosis-related RNAs and proteins including Nrf2 and Keap1, have shown to be differentially expressed in IDH-1 mutant cells at baseline via RT-qPCR. RNA analysis has shown overexpression of Nrf2 and Keap1, which are involved in redox balance, tumorigenesis, and resistance to anti-cancer therapies. In contrast, there is a significant decrease in the expression of Slc7a11, a crucial gene in cysteine and ferroptosis regulation and a known target of Nrf2.

Conclusion : In summary, our study is characterizing a new cell-based model for both WT and IDH1 mutant LGGs, emphasizing that ferroptosis is a critical cell death pathway differentiating these cells. This research could potentially provide novel therapies for IDH mutated cancers.