Nantes Université, Inserm 1307, CNRS 6075, Université d'Angers, Nantes, France.
Faculty of Sciences, Lebanese University, Beirut, Lebanon.
Neuro Oncol. 2024 Sep 5;26(9):1572-1586. doi: 10.1093/neuonc/noae106.
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.
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.
We showed that GSC-enriched cultures display distinct glycolytic profiles compared with differentiated tumor cells. Further analysis revealed that GSC relies on pyruvate carboxylase (PC) activity for survival and self-renewal capacity. Interestingly, inhibition of PC 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 PC restored etoposide sensitivity in GSC, both in vitro and in orthotopic murine models.
Our findings demonstrate the critical role of PC in GSC metabolism, survival, and escape to etoposide. They also highlight PC as a therapeutic target to overcome therapy resistance in GBM.
胶质母细胞瘤（GBM）是一种具有未满足治疗需求的高度侵袭性肿瘤，这可以用广泛的肿瘤内异质性和可塑性来解释。在这项研究中，我们旨在研究胶质母细胞瘤干细胞（GSC）的特定代谢特征，GSC 是一种参与肿瘤生长和治疗耐药的罕见肿瘤亚群。
我们使用最先进的分子、代谢和表型研究方法，对原发性患者来源的 GBM 培养物和人 GBM 细胞系的 GSC 富集培养物进行了全面分析。
我们表明，与分化的肿瘤细胞相比，GSC 富集培养物显示出明显的糖酵解特征。进一步的分析表明，GSC 依赖于丙酮酸羧化酶（PC）活性来维持生存和自我更新能力。有趣的是，抑制 PC 会导致 GSC 死亡，特别是当谷氨酰胺池较低且分化增加时。最后，虽然 GSC 对化疗药物依托泊苷具有耐药性，但 PC 的遗传或药理学抑制在体外和原位小鼠模型中恢复了 GSC 对依托泊苷的敏感性。
我们的研究结果表明 PC 在 GSC 代谢、存活和逃避依托泊苷方面发挥着关键作用。它们还强调了 PC 作为克服 GBM 治疗耐药性的治疗靶点的重要性。
