唾液酸代谢调控胶质母细胞瘤中的细胞间连接和信号转导。
Sialic acid metabolism orchestrates transcellular connectivity and signaling in glioblastoma.
机构信息
Microenvironment and Immunology Research Laboratory, Medical Center, University of Freiburg, Freiburg, Germany.
Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.
出版信息
Neuro Oncol. 2023 Nov 2;25(11):1963-1975. doi: 10.1093/neuonc/noad101.
BACKGROUND
In glioblastoma (GBM), the effects of altered glycocalyx are largely unexplored. The terminal moiety of cell coating glycans, sialic acid, is of paramount importance for cell-cell contacts. However, sialic acid turnover in gliomas and its impact on tumor networks remain unknown.
METHODS
We streamlined an experimental setup using organotypic human brain slice cultures as a framework for exploring brain glycobiology, including metabolic labeling of sialic acid moieties and quantification of glycocalyx changes. By live, 2-photon and high-resolution microscopy we have examined morphological and functional effects of altered sialic acid metabolism in GBM. By calcium imaging we investigated the effects of the altered glycocalyx on a functional level of GBM networks.
RESULTS
The visualization and quantitative analysis of newly synthesized sialic acids revealed a high rate of de novo sialylation in GBM cells. Sialyltrasferases and sialidases were highly expressed in GBM, indicating that significant turnover of sialic acids is involved in GBM pathology. Inhibition of either sialic acid biosynthesis or desialylation affected the pattern of tumor growth and lead to the alterations in the connectivity of glioblastoma cells network.
CONCLUSIONS
Our results indicate that sialic acid is essential for the establishment of GBM tumor and its cellular network. They highlight the importance of sialic acid for glioblastoma pathology and suggest that dynamics of sialylation have the potential to be targeted therapeutically.
背景
在神经胶质瘤（GBM）中，糖萼改变的影响在很大程度上尚未被探索。细胞涂层聚糖的末端部分，唾液酸，对于细胞-细胞接触至关重要。然而，神经胶质瘤中的唾液酸周转率及其对肿瘤网络的影响仍然未知。
方法
我们使用器官型人脑切片培养作为探索脑糖生物学的框架，简化了实验设置，包括唾液酸部分的代谢标记和糖萼变化的定量。通过活细胞、双光子和高分辨率显微镜，我们研究了改变的唾液酸代谢对 GBM 的形态和功能的影响。通过钙成像，我们研究了改变的糖萼对 GBM 网络功能水平的影响。
结果
新合成的唾液酸的可视化和定量分析显示 GBM 细胞中存在高的从头唾液酸化率。唾液酸转移酶和唾液酸酶在 GBM 中高度表达，表明唾液酸的大量周转参与了 GBM 病理学。抑制唾液酸的生物合成或去唾液酸化都会影响肿瘤生长的模式，并导致神经胶质瘤细胞网络连接的改变。
结论
我们的结果表明，唾液酸对于 GBM 肿瘤及其细胞网络的建立是必不可少的。它们突出了唾液酸对神经胶质瘤病理学的重要性，并表明唾液酸化的动态具有成为治疗靶点的潜力。
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