Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
Department of Basic Medical Sciences, Faculty of Medicine, The Hashemite University, Zarqa, Jordan.
Life Sci Alliance. 2021 Oct 13;4(12). doi: 10.26508/lsa.202101054. Print 2021 Dec.
Better understanding of GBM signalling networks in-vivo would help develop more physiologically relevant ex vivo models to support therapeutic discovery. A "functional proteomics" screen was undertaken to measure the specific activity of a set of protein kinases in a two-step cell-free biochemical assay to define dominant kinase activities to identify potentially novel drug targets that may have been overlooked in studies interrogating GBM-derived cell lines. A dominant kinase activity derived from the tumour tissue, but not patient-derived GBM stem-like cell lines, was Bruton tyrosine kinase (BTK). We demonstrate that BTK is expressed in more than one cell type within GBM tissue; SOX2-positive cells, CD163-positive cells, CD68-positive cells, and an unidentified cell population which is SOX2-negative CD163-negative and/or CD68-negative. The data provide a strategy to better mimic GBM tissue ex vivo by reconstituting more physiologically heterogeneous cell co-culture models including BTK-positive/negative cancer and immune cells. These data also have implications for the design and/or interpretation of emerging clinical trials using BTK inhibitors because BTK expression within GBM tissue was linked to longer patient survival.
更好地了解 GBM 信号转导网络体内情况将有助于开发更具生理相关性的离体模型，以支持治疗发现。进行了“功能蛋白质组学”筛选，以两步无细胞生化测定来测量一组蛋白激酶的特定活性，从而定义主导激酶活性，以鉴定可能在研究 GBM 衍生细胞系时被忽视的潜在新药物靶点。源自肿瘤组织但不是源自患者衍生的 GBM 类干细胞系的优势激酶活性来自布鲁顿酪氨酸激酶 (BTK)。我们证明 BTK 在 GBM 组织中的一种以上细胞类型中表达;SOX2 阳性细胞、CD163 阳性细胞、CD68 阳性细胞和一种未识别的细胞群，该细胞群既不是 SOX2 阴性也不是 CD163 阴性和/或 CD68 阴性。这些数据提供了一种更好地模拟 GBM 组织离体的策略，通过重建更具生理异质性的细胞共培养模型，包括 BTK 阳性/阴性癌症和免疫细胞。这些数据对于使用 BTK 抑制剂设计和/或解释新兴临床试验也具有意义，因为 BTK 在 GBM 组织中的表达与患者生存时间延长有关。
