Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; USC Brain Tumor Center, University of Southern California, Los Angeles, CA 90089, USA.
Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA 90089, USA.
Cell Rep. 2021 Jun 29;35(13):109302. doi: 10.1016/j.celrep.2021.109302.
Medulloblastoma (MB) is a malignant pediatric brain tumor arising in the cerebellum. Although abnormal GABAergic receptor activation has been described in MB, studies have not yet elucidated the contribution of receptor-independent GABA metabolism to MB pathogenesis. We find primary MB tumors globally display decreased expression of GABA transaminase (ABAT), the protein responsible for GABA metabolism, compared with normal cerebellum. However, less aggressive WNT and SHH subtypes express higher ABAT levels compared with metastatic G3 and G4 tumors. We show that elevated ABAT expression results in increased GABA catabolism, decreased tumor cell proliferation, and induction of metabolic and histone characteristics mirroring GABAergic neurons. Our studies suggest ABAT expression fluctuates depending on metabolite changes in the tumor microenvironment, with nutrient-poor conditions upregulating ABAT expression. We find metastatic MB cells require ABAT to maintain viability in the metabolite-scarce cerebrospinal fluid by using GABA as an energy source substitute, thereby facilitating leptomeningeal metastasis formation.
髓母细胞瘤（MB）是一种起源于小脑的恶性小儿脑肿瘤。尽管已经描述了 MB 中异常 GABA 能受体的激活，但研究尚未阐明受体非依赖性 GABA 代谢对 MB 发病机制的贡献。我们发现与正常小脑相比，原发性 MB 肿瘤整体上显示 GABA 转氨酶（ABAT）表达降低，ABAT 是负责 GABA 代谢的蛋白质。然而，侵袭性较低的 WNT 和 SHH 亚型与转移性 G3 和 G4 肿瘤相比表达更高的 ABAT 水平。我们表明，ABAT 表达的升高导致 GABA 分解代谢增加、肿瘤细胞增殖减少，并诱导代谢和组蛋白特征类似于 GABA 能神经元。我们的研究表明，ABAT 的表达取决于肿瘤微环境中代谢物的变化，营养匮乏的条件上调 ABAT 的表达。我们发现转移性 MB 细胞通过将 GABA 用作能量源替代物来维持在代谢物匮乏的脑脊液中的存活能力，从而促进软脑膜转移的形成。
