ER –mitochondria contacts control surface glycan expression and sensitivity to killer lymphocytes in glioma stem‐like cells

Abstract

Glioblastoma is a highly heterogeneous aggressive primary brain tumor, with the glioma stem‐like cells ( GSC ) being more sensitive to cytotoxic lymphocyte‐mediated killing than glioma differentiated cells ( GDC ). However, the mechanism behind this higher sensitivity is unclear. Here, we found that the mitochondrial morphology of GSC s modulates the ER –mitochondria contacts that regulate the surface expression of sialylated glycans and their recognition by cytotoxic T lymphocytes and natural killer cells. GSC s displayed diminished ER –mitochondria contacts compared to GDC s. Forced ER –mitochondria contacts in GSC s increased their cell surface expression of sialylated glycans and reduced their susceptibility to cytotoxic lymphocytes. Therefore, mitochondrial morphology and dynamism dictate the ER –mitochondria contacts in order to regulate the surface expression of certain glycans and thus play a role in GSC recognition and elimination by immune effector cells. Targeting the mitochondrial morphology, dynamism, and contacts with the ER could be an innovative strategy to deplete the cancer stem cell compartment to successfully treat glioblastoma. image Increased susceptibility of glioma stem‐like cells ( GSC ) to immune effector cells in brain tumors is caused by enhanced mitochondrial dynamics dictating reduced ER –mitochondria tethering and surface expression of glycans. GSC s possess short and highly dynamic mitochondria compared to their glioma differentiated cell ( GDC ) counterparts. Fragmentation of mitochondria and the number of ER –mitochondria contacts regulate sialylated glycan surface expression in glioma cells. GSC s exhibit fewer ER –mitochondrial contacts resulting in reduced surface expression of glycans. Diminished glycan surface expression increases glioma cell sensitivity to cytotoxic lymphocytes.