Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.
Nature. 2020 Feb;578(7793):166-171. doi: 10.1038/s41586-020-1952-2. Epub 2020 Jan 29.
Glioblastoma is a universally lethal form of brain cancer that exhibits an array of pathophysiological phenotypes, many of which are mediated by interactions with the neuronal microenvironment. Recent studies have shown that increases in neuronal activity have an important role in the proliferation and progression of glioblastoma. Whether there is reciprocal crosstalk between glioblastoma and neurons remains poorly defined, as the mechanisms that underlie how these tumours remodel the neuronal milieu towards increased activity are unknown. Here, using a native mouse model of glioblastoma, we develop a high-throughput in vivo screening platform and discover several driver variants of PIK3CA. We show that tumours driven by these variants have divergent molecular properties that manifest in selective initiation of brain hyperexcitability and remodelling of the synaptic constituency. Furthermore, secreted members of the glypican (GPC) family are selectively expressed in these tumours, and GPC3 drives gliomagenesis and hyperexcitability. Together, our studies illustrate the importance of functionally interrogating diverse tumour phenotypes driven by individual, yet related, variants and reveal how glioblastoma alters the neuronal microenvironment.
胶质母细胞瘤是一种普遍致命的脑癌，表现出多种病理生理表型，其中许多是由与神经元微环境相互作用介导的。最近的研究表明，神经元活动的增加在胶质母细胞瘤的增殖和进展中起着重要作用。胶质母细胞瘤和神经元之间是否存在相互交流仍然知之甚少，因为尚不清楚这些肿瘤将神经元环境重塑为增加活性的机制。在这里，我们使用胶质母细胞瘤的天然小鼠模型，开发了一种高通量体内筛选平台，并发现了几种 PIK3CA 的驱动变体。我们表明，由这些变体驱动的肿瘤具有不同的分子特性，表现为大脑过度兴奋的选择性起始和突触组成的重塑。此外，糖蛋白 (GPC) 家族的分泌成员在这些肿瘤中选择性表达，GPC3 驱动神经胶质瘤的发生和过度兴奋。总之，我们的研究说明了对由单个但相关变体驱动的不同肿瘤表型进行功能研究的重要性，并揭示了胶质母细胞瘤如何改变神经元微环境。
