Mitochondrial transfer from astrocytes to glioblastoma cells drives tumor growth - PROJECT SUMMARY: Glioblastoma (GBM) is the most common primary brain tumor and is incurable, invariably recuring after standard therapy with surgery, chemotherapy and radiation. GBM cell heterogeneity allows it to thrive in varying adverse conditions in the tumor microenvironment (TME), including therapeutic insults, hypoxic stress, and immune attack. Interactions with cells in the TME—including neurons, glia, endothelium, and immune cells—support this heterogeneity and plasticity, contributing to the tumorigenicity, resistance, and recurrence of this deadly disease. Given the limited efficacy of standard treatment approaches in GBM, there is an urgent need to decipher and therapeutically target protumorigenic interactions in the TME. There is evidence that glioma cells form an interconnected network that facilitates the exchange of mitochondria, which are the main energy-producing organelle and regulate metabolism, proliferation, and epigenetics. There is also early evidence that mitochondria can be transferred from non-malignant cells to cancer cells. However, there is limited understanding of mitochondrial transfer dynamics from the TME to GBM; the mechanisms that govern this transfer; and the downstream effects of transfer on recipient GBM cells. Addressing this knowledge gap is vital for designing therapeutics that target this interaction. I hypothesize that mitochondria are transferred from neural cells in the TME to GBM by the action of fusogenic proteins, and that this transfer drives tumorigenicity by metabolic and epigenetic reprogramming. Specific Aim 1 will test the hypothesis that astrocytes are the predominant mitochondrial donors, and that transfer is mediated by fusogenic proteins termed syncytins. I will investigate mitochondrial donor identity using transgenic mice and cell models expressing lineage-specific mitochondrial fluorophores. I will test how knockdown and overexpression of syncytins affects rate and protumorigenic effects of transfer from astrocytes to GBM cells. Specific Aim 2 will test the hypothesis that mitochondrial transfer from astrocytes drives GBM proliferation and tumorigenicity by metabolic and epigenetic reprogramming. I will investigate how transfer of ATP-synthase with mitochondria drives tumorigenicity; how mitochondrial transfer results in plasticity of GBM heterogeneity by global metabolic reprogramming; and how mitochondrial transfer drives proliferation by epigenetic reprogramming and increased chromatin accessibility. Career development and long-term objectives: I will receive training in cancer metabolism and brain tumor research, and interact with a mentorship committee of experts from both fields. This training and the proposed studies are invaluable for my career goal of establishing an independent research program with the following long-term objectives: (a) elucidate molecular mechanisms of how mitochondrial transfer reprograms metabolism and epigenetics, (b) develop therapeutics targeting mitochondrial transfer and its downstream effects, (c) investigate how metabolic interactions in the TME impact other treatment modalities, including chemotherapy, radiotherapy, and immunotherapy in GBM and other cancers.
