Determining the Role of Lipid Droplets in Resistance to Ferroptosis in DIPG
Mentor: Costas Lyssiotis
Diffuse intrinsic pontine glioma (DIPG) is the deadliest brainstem cancer in children, and significant therapeutic progress has not been made in decades. The standard of care is focal radiation therapy to the pons, which serves mostly to alleviate symptoms. So far, no chemotherapeutic agent has been found successful at improving survival outcomes beyond radiation therapy alone. Therefore, there is an urgent need to identify new treatment strategies for DIPG. Several reports, including studies from the Lyssiotis Lab, have shown that tumor cells that are resistant to pro-apoptotic chemotherapy conversely become more sensitive to a non-apoptotic and oxidative form of cell death termed “ferroptosis”. Ferroptosis is an iron-dependent form of cell death mediated by the accumulation of toxic lipid peroxides that can be induced by blocking the pathways that manage lipid ROS. Ferroptosis can be induced by depleting glutathione (GSH) in cells via inhibition of cysteine import into the cells, inhibition of GSH synthesis, or by mechanisms involving direct inhibition of the GSH-dependent lipid peroxidase GPX4. Induction of ferroptosis is cytotoxic to cancer cells in vitro and inhibits tumor growth in vivo. Applying these concepts, we found that patient-derived DIPG cells are profoundly sensitive to inducers of ferroptosis when the cells are cultured in vitro in ‘serum-containing media’ that induces a differentiated state (adherent cells). In contrast, when DIPG cells are cultured in ‘tumor stem cell media’ supplemented with growth factors, which gives rise to tumor stem-like cells (neurospheres), there is a markedly decreased sensitivity to ferroptosis. This therefore suggests that DIPG tumor stem-like cells harbor intrinsic metabolic alterations that protect these cells against the toxic effects of ferroptosis. Perturbations in lipid metabolic pathways have been shown to influence sensitivity to ferroptosis. Accordingly, the increased formation and accumulation of intracellular lipid droplets have been reported to protect neural stems cells from the damaging effects of lipid peroxidation. We thereby hypothesize that increased formation and accumulation of lipid droplets in DIPG neurospheres in response to ferroptosis inducers is the cause of ferroptosis-resistance in neurospheres. Therefore, the goal of Daniella Maydan’s undergraduate summer research project is to determine the role of intracellular lipid droplets in mediating the resistance of the DIPG neurospheres to ferroptosis. The outcome of this study will provide the basis for future evaluation of the potential utility of combined targeting of lipid droplets and ferroptosis in DIPG.
