Koch Marilin S, Deo Minh, Schmitt Lena-Marie, Hoetker Michael S, Turcan Şevin
Clinical Cooperation Unit Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Neurology and Neurooncology, University Hospital Heidelberg and National Center for Tumor Diseases, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Acta Neuropathol Commun. 2025 Apr 30;13(1):87. doi: 10.1186/s40478-025-02006-y.
Mutations in isocitrate dehydrogenase (IDH)1/2 are defining drivers of low-grade gliomagenesis. However, mutant IDH alone is not sufficient for malignant transformation, and additional events are required for the development of low-grade glioma. While specific genetic lesions have been identified to contribute to low-grade gliomagenesis, less is known about the signaling pathways involved in the acquisition of malignancy. To identify prerequisites of IDH mutant tumorigenesis, we modulated pathways previously implicated in glioma initiation using a tractable in vitro model system for early IDH1-dependent gliomagenesis. Through the use of chemical compounds, we targeted WNT/GSK3, TGF-β and NOTCH-signaling, assessing their functional, transcriptional, and translational impacts. Expression of LGG-related marker L1CAM was affected by perturbation of all pathways, though only modulation of WNT/GSK3-signaling resulted in profound molecular transformation, including glioma-associated genes and programs regulating cellular architecture and cell replication. This was accompanied by altered cell morphology, migration capacity, and enhanced proliferation. Transcription factor RUNX2 was identified as a potential downstream effector, whose inhibition abrogated cell proliferation. Disrupted WNT/GSK3 signaling in a model system of early low-grade gliomagenesis fundamentally impacted cell fate, as demonstrated by a reshaped transcriptional landscape, aberrant transcription factor activity, extracellular matrix restructuring, and altered proliferation capacity. Our data suggests that GSK3 may play a central role during low-grade gliomagenesis, warranting further investigation.
异柠檬酸脱氢酶（IDH）1/2的突变是低级别胶质瘤发生的决定性驱动因素。然而，单纯的IDH突变不足以导致恶性转化，低级别胶质瘤的发展还需要其他事件。虽然已经确定了一些特定的基因损伤有助于低级别胶质瘤的发生，但对于恶性肿瘤形成过程中涉及的信号通路了解较少。为了确定IDH突变肿瘤发生的先决条件，我们使用了一种易于处理的体外模型系统，该系统用于早期IDH1依赖性胶质瘤发生，调节先前与胶质瘤起始相关的信号通路。通过使用化学化合物，我们靶向WNT/GSK3、TGF-β和NOTCH信号通路，评估它们的功能、转录和翻译影响。LGG相关标志物L1CAM的表达受到所有信号通路扰动的影响，尽管只有WNT/GSK3信号通路的调节导致了深刻的分子转化，包括胶质瘤相关基因以及调节细胞结构和细胞复制的程序。这伴随着细胞形态、迁移能力的改变以及增殖的增强。转录因子RUNX2被确定为一个潜在的下游效应器，其抑制作用消除了细胞增殖。在早期低级别胶质瘤发生的模型系统中，WNT/GSK3信号通路的破坏从根本上影响了细胞命运，这表现为重塑的转录图谱、异常的转录因子活性、细胞外基质重塑以及增殖能力的改变。我们的数据表明，GSK3可能在低级别胶质瘤发生过程中起核心作用，值得进一步研究。
