RESUMEN
BACKGROUND: Glioblastoma (GBM) is a highly aggressive tumor with unmet therapeutic needs, which can be explained by extensive intra-tumoral heterogeneity and plasticity. In this study, we aimed to investigate the specific metabolic features of Glioblastoma stem cells (GSC), a rare tumor subpopulation involved in tumor growth and therapy resistance. METHODS: We conducted comprehensive analyses of primary patient-derived GBM cultures and GSC-enriched cultures of human GBM cell lines using state-of-the-art molecular, metabolic and phenotypic studies. RESULTS: We showed that GSC-enriched cultures display distinct glycolytic profiles compared with differentiated tumor cells. Further analysis revealed that GSC relies on pyruvate carboxylase activity for survival and self-renewal capacity. Interestingly, inhibition of pyruvate carboxylase led to GSC death, particularly when the glutamine pool was low, and increased differentiation. Finally, while GSC displayed resistance to the chemotherapy drug etoposide, genetic or pharmacological inhibition of pyruvate carboxylase restored etoposide sensitivity in GSC, both in vitro and in orthotopic murine models. CONCLUSION: Our findings demonstrate the critical role of pyruvate carboxylase in GSC metabolism, survival and escape to etoposide. They also highlight pyruvate carboxylase as a therapeutic target to overcome therapy resistance in GBM.
RESUMEN
Cancer treatment protocols depend on tumor type, localization, grade, and patient. Despite aggressive treatments, median survival of patients with Glioblastoma (GBM), the most common primary brain tumor in adults, does not exceed 18 months, and all patients eventually relapse. Thus, novel therapeutic approaches are urgently needed. Radiotherapy (RT) induces a multitude of alterations within the tumor ecosystem, ultimately modifying the degree of tumor immunogenicity at GBM relapse. The present manuscript reviews the diverse effects of RT radiotherapy on tumors, with a special focus on its immunomodulatory impact to finally discuss how RT could be exploited in GBM treatment through immunotherapy targeting. Indeed, while further experimental and clinical studies are definitively required to successfully translate preclinical results in clinical trials, current studies highlight the therapeutic potential of immunotherapy to uncover novel avenues to fight GBM.