Role of ER Stress and Fatty Acid Metabolism in Glioma Stem Cells

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Abstract Glioblastoma is the most malignant and common form of primary central nervous system tumors with high mortality and resistance to therapy. The presence of Glioma stem cells (GSCs) within the tumor, further complicates treatment, owing to the role of GSCs in promoting therapeutic resistance and tumor recurrence. Identifying Intrinsic and extrinsic factors that contribute to GSCs maintenance thus influencing tumor growth, could offer new therapeutic opportunities to treat this fatal disease. We recently showed that the desaturation of fatty acids (FA) is essential for maintaining GSCs self-renewal, proliferation, and in vivo tumor initiation properties. Pharmacological targeting of the desaturase enzyme Stearoyl CoA Desaturase 1 (SCD1) is particularly toxic due to the accumulation of saturated FA, which promotes apoptotic cell death, and achieves a remarkable therapeutic outcome in xenograft mouse models. Our results demonstrate that the dependence of GSCs on FA desaturation presents an exploitable vulnerability to target glioblastoma. However, regulation mechanisms driving key lipogenic enzymes such as SCD1, as well as the molecular role of FA in GSCs maintenance and plasticity remains unclear. Based on our preliminary results, we propose that stress signaling through the endoplasmic reticulum (ER stress), promotes the transcriptional activation of SCD1 as well as oncogenic signaling pathways downstream of SCD1 that are essential for GSCs maintenance. The objective of this proposal is to: 1) Define the role of ER stress in activating lipogenesis and oncogenic signaling that promote GSC self-renewal and increase tumorigenic potential. 2) Exploit the dependency of GSCs on adaptive ER stress signaling to test targeted therapeutics in patient-derived orthotopic GSCs mouse models. Upon completion, this work will elucidate novel mechanisms of plasticity and survival in GBM cancer stem cells and identify novel targeted therapeutics for clinical evaluation in GBM patients.