Department of Neurology and Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
Neuro Oncol. 2023 Feb 14;25(2):290-302. doi: 10.1093/neuonc/noac169.
Recent efforts have described the evolution of glioblastoma from initial diagnosis to post-treatment recurrence on a genomic and transcriptomic level. However, the evolution of the proteomic landscape is largely unknown.
Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) was used to characterize the quantitative proteomes of two independent cohorts of paired newly diagnosed and recurrent glioblastomas. Recurrence-associated proteins were validated using immunohistochemistry and further studied in human glioma cell lines, orthotopic xenograft models, and human organotypic brain slice cultures. External spatial transcriptomic, single-cell, and bulk RNA sequencing data were analyzed to gain mechanistic insights.
Although overall proteomic changes were heterogeneous across patients, we identified BCAS1, INF2, and FBXO2 as consistently upregulated proteins at recurrence and validated these using immunohistochemistry. Knockout of FBXO2 in human glioma cells conferred a strong survival benefit in orthotopic xenograft mouse models and reduced invasive growth in organotypic brain slice cultures. In glioblastoma patient samples, FBXO2 expression was enriched in the tumor infiltration zone and FBXO2-positive cancer cells were associated with synaptic signaling processes.
These findings demonstrate a potential role of FBXO2-dependent glioma-microenvironment interactions to promote tumor growth. Furthermore, the published datasets provide a valuable resource for further studies.
最近的研究已经描述了从初始诊断到治疗后复发的胶质母细胞瘤在基因组和转录组水平上的演变。然而，蛋白质组景观的演变在很大程度上是未知的。
采用连续窗口获取所有理论片段离子谱质谱（SWATH-MS）的方法，对两个独立队列的配对新诊断和复发性胶质母细胞瘤的定量蛋白质组进行了特征描述。使用免疫组织化学法验证了与复发相关的蛋白质，并在人神经胶质瘤细胞系、原位异种移植模型和人器官型脑片培养物中进一步研究了这些蛋白质。分析了外部空间转录组、单细胞和批量 RNA 测序数据，以获得机制见解。
尽管患者之间的整体蛋白质组变化存在异质性，但我们发现 BCAS1、INF2 和 FBXO2 是复发时一致上调的蛋白质，并通过免疫组织化学法进行了验证。在人神经胶质瘤细胞中敲除 FBXO2 ，在原位异种移植小鼠模型中赋予了强烈的生存获益，并减少了器官型脑片培养物中的侵袭性生长。在胶质母细胞瘤患者样本中，FBXO2 表达在肿瘤浸润区富集，FBXO2 阳性癌细胞与突触信号转导过程有关。
这些发现表明 FBXO2 依赖性胶质瘤-微环境相互作用在促进肿瘤生长方面可能具有潜在作用。此外，已发表的数据集为进一步的研究提供了有价值的资源。
