Astrocytes donate mitochondria to increase glioblastoma tumorigenicity

Abstract Glioblastoma (GBM), the most common primary brain cancer in adults1, is characterized by numerous cell-intrinsic/extrinsic interactions that drive tumorigenesis. In addition to cell-surface and secreted protein/extracellular vesicle interactions2,3, treatment resistance of GBM is augmented by the formation of cytoplasmic interconnections and junctions among tumor cells4. These cytoplasmic bridges among tumor cells enable exchange of cellular metabolites as well as mitochondria4, which can play a key role in metabolic function and cellular programming in GBM5,6. However, the contribution of the tumor microenvironment to mitochondrial transfer, as well as the downstream impact of mitochondrial transfer on GBM remains poorly characterized. Here we identified horizontal mitochondrial transfer from the tumor microenvironment as a mechanism that enhances tumorigenesis in glioblastoma. We found that this transfer occurs primarily from brain-resident cells, including astrocytes, and can be appreciated in vitro and in vivo through intercellular connections between GBM cells and non-malignant host cells. The acquisition of astrocyte mitochondria drives an overall enhancement of mitochondrial membrane potential and metabolic capacity, while increasing glioblastoma cell self-renewal and tumor-initiating capacity. Collectively, our findings demonstrate that astrocyte mitochondrial transfer augments the tumorigenic capacity of glioblastoma cells and reveals a previously unknown cell-cell communication mechanism that drives tumor growth. We anticipate our findings will open new research directions to decipher the molecular events linking mitochondria acquisition from non-malignant cells to increased tumorigenicity of recipient GBM cells. This line of research will lead to new therapeutic opportunities targeting this understudied phenomenon and its sequelae in GBM.