在体功能表征鉴定出了胶质母细胞瘤的新型驱动基因。
In vivo functional characterization of EGFR variants identifies novel drivers of glioblastoma.
机构信息
Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, 77030, USA.
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, 77030, USA.
出版信息
Neuro Oncol. 2023 Mar 14;25(3):471-481. doi: 10.1093/neuonc/noac215.
BACKGROUND
Glioblastoma is the most common and aggressive primary brain tumor. Large-scale sequencing initiatives have cataloged its mutational landscape in hopes of elucidating mechanisms driving this deadly disease. However, a major bottleneck in harnessing this data for new therapies is deciphering "driver" and "passenger" events amongst the vast volume of information.
METHODS
We utilized an autochthonous, in vivo screening approach to identify driver, EGFR variants. RNA-Seq identified unique molecular signatures of mouse gliomas across these variants, which only differ by a single amino acid change. In particular, we identified alterations to lipid metabolism, which we further validated through an unbiased lipidomics screen.
RESULTS
Our screen identified A289I as the most potent EGFR variant, which has previously not been characterized. One of the mechanisms through which A289I promotes gliomagenesis is to alter cellular triacylglycerides through MTTP. Knockout of Mttp in mouse gliomas, reduces gliomagenesis in multiple models.
CONCLUSIONS
EGFR variants that differ by a single amino acid residue differentially promote gliomagenesis. Among the identified mechanism that drives glioma growth include lipid metabolism through MTTP. Understanding triacylglyceride accumulation may present a prospective therapeutic pathway for this deadly disease.
背景
胶质母细胞瘤是最常见和最具侵袭性的原发性脑肿瘤。大规模测序计划已经对其突变景观进行了编目，以期阐明驱动这种致命疾病的机制。然而，利用这些数据为新疗法开发的一个主要瓶颈是破译大量信息中的“驱动”和“乘客”事件。
方法
我们利用一种自发的、体内筛选方法来鉴定 EGFR 变体的驱动因素。RNA-Seq 确定了这些变体之间的独特分子特征，这些变体仅在单个氨基酸变化上有所不同。特别是，我们确定了脂质代谢的改变，我们通过一个无偏的脂质组学筛选进一步验证了这一点。
结果
我们的筛选确定了 A289I 作为最有效的 EGFR 变体，以前没有对其进行过特征描述。A289I 促进神经胶质瘤发生的机制之一是通过 MTTP 改变细胞三酰甘油。在多种模型中敲除 MTTP 可减少小鼠神经胶质瘤的发生。
结论
仅在单个氨基酸残基上有所不同的 EGFR 变体可促进神经胶质瘤的发生。驱动胶质瘤生长的机制包括通过 MTTP 进行脂质代谢。了解三酰甘油的积累可能为这种致命疾病提供一个有前景的治疗途径。
Zotero 插件