Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, 114, Taiwan.
Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, 114, Taiwan.
Mol Neurobiol. 2019 Jun;56(6):4589-4599. doi: 10.1007/s12035-018-1392-2. Epub 2018 Oct 24.
Glioblastoma multiforme (GBM), the most prevalent brain tumor in adults, has extremely poor prognosis. Frequent genetic alterations that activate epidermal growth factor receptor (EGFR) and phosphatidylinositol-3 kinase (PI3K) signaling, as well as metabolic remodeling, have been associated with gliomagenesis. To establish a whole-animal approach that can be used to readily identify individual pathometabolic signaling factors, we induced glioma formation in the adult Drosophila brain by activating the EGFR-PI3K pathway. Glioma-induced animals showed significantly enlarged brain volume, early locomotor abnormalities, memory deficits, and a shorter lifespan. Combining bioinformatics analysis and glial-specific gene knockdown in the adult fly glioma model, we identified four evolutionarily conserved metabolic genes, including ALDOA, ACAT1, ELOVL6, and LOX, that were involved in gliomagenesis. Silencing of ACAT1, which controls cholesterol homeostasis, reduced brain enlargement and increased the lifespan of the glioma-bearing flies. In GBM patients, ACAT1 is overexpressed and correlates with poor survival outcomes. Moreover, pharmacological inhibition of ACAT1 in human glioma cell lines revealed that it is essential for tumor proliferation. Collectively, these results imply that ACAT1 is a potential therapeutic target, and cholesterol homeostasis is strongly related to glioma formation. This in vivo model provides several rapid and robust phenotypic readouts, allowing determination of the pathometabolic pathways involved in gliomagenesis, as well as providing valuable information for novel therapeutic strategies.
多形性胶质母细胞瘤（GBM）是成人中最常见的脑肿瘤，预后极差。频繁的基因改变激活了表皮生长因子受体（EGFR）和磷脂酰肌醇-3 激酶（PI3K）信号通路，以及代谢重塑，与神经胶质瘤的发生有关。为了建立一种可以轻易识别个体病理代谢信号因子的整体动物方法，我们通过激活 EGFR-PI3K 通路在成年果蝇大脑中诱导形成神经胶质瘤。神经胶质瘤诱导的动物表现出明显增大的脑体积、早期运动异常、记忆缺陷和寿命缩短。通过对成年果蝇神经胶质瘤模型中的生物信息学分析和神经胶质特异性基因敲低相结合，我们鉴定出四个进化上保守的代谢基因，包括 ALDOA、ACAT1、ELOVL6 和 LOX，它们参与了神经胶质瘤的发生。沉默控制胆固醇稳态的 ACAT1 可减少脑肿大并延长携带神经胶质瘤的果蝇的寿命。在 GBM 患者中，ACAT1 过表达，与不良生存结果相关。此外，在人神经胶质瘤细胞系中抑制 ACAT1 的药理作用表明，它对肿瘤增殖是必需的。总之，这些结果表明 ACAT1 是一个潜在的治疗靶点，胆固醇稳态与神经胶质瘤的形成密切相关。这种体内模型提供了几种快速而强大的表型检测，可确定涉及神经胶质瘤发生的病理代谢途径，并为新的治疗策略提供有价值的信息。
