INTER-ORGANELLE COMMUNICATION IN CANCER: THE ROLE OF ER-MITOCHONDRIA CONTACT SITES IN GLIOBLASTOMA

Glioblastoma (GBM) is one of the most frequent and deadliest primary brain tumors. Although GBM has been documented since the 1920s, only four FDA-approved drugs and devices specific for the treatment of glioblastoma have been produced. Still, none of these succeeded in significantly extending patient lives beyond a few extra months, and GBM remains a death sentence. Glioma stem-like cells (GSCs) have been recognized as the main reason for the failure of therapeutic approaches and for tumor recurrence. Any rational improvement in treatment protocol must target GSCs to have a chance of success. In cancer, as in many other pathological condition, inter-organelle communication is altered, providing cancer cells with increased adaptability and survival. In line with that, we have previously demonstrated that mitochondria morphology and its contacts with the endoplasmic reticulum, through the mitochondria-ER contact sites (MERCs), dictate the topology of GBM cells’ plasma membrane and susceptibility to cytotoxic T lymphocytes. Taking these data into account, during my PhD project, I investigated the role of the MERCs in GBM cell susceptibility to chemo- and radiotherapy. MERCs regulate different crucial aspects of cellular homeostasis, and therefore, we hypothesized that altering this communication could be beneficial for disrupting cancer cell biology. Our results demonstrate that the chemical modulation of MERCs is not only able to reduce the proliferation, invasion, and migration of GBM cells, but also to potentiate the cytotoxicity of standard and emerging chemotherapies and radiotherapy. Importantly, these chemical MERC modulators efficiently decreased invasiveness and increased the sensitivity to chemo- and radiotherapy of GSCs, which are otherwise particularly resistant to standard treatments alone. Collectively, the results obtained in the present work pave the way for exciting new investigations aimed at evaluating the feasibility of these treatments in vivo, and at characterizing the molecular mechanism through which MERC modulators interfere with glioma cells susceptibility to therapies.