Molecular, Cellular and Developmental Biology (MCD), Center for Integrative Biology (CBI), University of Toulouse, CNRS, UPS, 118 route de Narbonne, 31062, Toulouse, France.
Molecular, Cellular and Developmental Biology (MCD), Center for Integrative Biology (CBI), University of Toulouse, CNRS, UPS, 118 route de Narbonne, 31062, Toulouse, France.
Cancer Lett. 2021 Apr 10;503:129-137. doi: 10.1016/j.canlet.2021.01.026. Epub 2021 Feb 2.
Brain tumors are a heterogeneous group of benign and malignant tumors arising from the brain parenchyma and its surrounding structures, with in general a poor clinical outcome due to high recurrence. One of the underlying causes for this somber prognostic is the presence of brain tumor initiating cells (BTIC) endowed with self-renewal potential, multi-lineage differentiation and resistance to treatment. One promising therapeutic avenue for brain tumors is targeting BTIC self-renewal potential and forcing their differentiation. A compelling candidate is one-carbon metabolism shown to play a key role in maintaining stem cell self-renewal in several lineages. Here, we focus on dihydrofolate reductase (DHFR), a key enzyme in one-carbon metabolism, and demonstrate this enzyme's overexpression in several human brain tumors and its expression in human BTIC. We show that DHFR inhibition, either by Methotrexate (MTX) or EphB activation with synthetic ligands, reduces the tumorigenic potential of 4 human BTIC lines, by reducing their self-renewal capacities both in vitro and in a cerebral organoid glioma (GLICO) model. Our data indicate that driving BTIC differentiation by inhibiting DHFR may provide a new therapeutic approach to treating highly refractory aggressive tumors.
脑肿瘤是一组源自脑实质及其周围结构的良性和恶性肿瘤，由于高复发率，总体临床预后较差。导致这种预后不佳的一个潜在原因是存在具有自我更新能力、多能分化和耐药性的脑肿瘤起始细胞（BTIC）。针对 BTIC 自我更新潜力并促使其分化是一种有前途的治疗方法。一碳代谢被证明在维持多个谱系的干细胞自我更新中起着关键作用，是一个很有前途的候选方法。在这里，我们专注于二氢叶酸还原酶（DHFR），它是一碳代谢中的关键酶，并证明该酶在几种人类脑肿瘤中过度表达，并在人类 BTIC 中表达。我们表明，DHFR 抑制，无论是通过甲氨蝶呤（MTX）还是通过合成配体激活 EphB，都可以通过减少它们的自我更新能力，无论是在体外还是在大脑类器官胶质瘤（GLICO）模型中，都可以降低 4 个人类 BTIC 系的肿瘤发生潜力。我们的数据表明，通过抑制 DHFR 驱动 BTIC 分化可能为治疗高度难治性侵袭性肿瘤提供一种新的治疗方法。
