Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany.
Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany.
Cell Death Dis. 2021 Jul 21;12(8):723. doi: 10.1038/s41419-021-03937-9.
Glioblastoma (GBM), the most malignant tumor of the central nervous system, is marked by its dynamic response to microenvironmental niches. In particular, this cellular plasticity contributes to the development of an immediate resistance during tumor treatment. Novel insights into the developmental trajectory exhibited by GBM show a strong capability to respond to its microenvironment by clonal selection of specific phenotypes. Using the same mechanisms, malignant GBM do develop intrinsic mechanisms to resist chemotherapeutic treatments. This resistance was reported to be sustained by the paracrine and autocrine glutamate signaling via ionotropic and metabotropic receptors. However, the extent to which glutamatergic signaling modulates the chemoresistance and transcriptional profile of the GBM remains unexplored. In this study we aimed to map the manifold effects of glutamate signaling in GBM as the basis to further discover the regulatory role and interactions of specific receptors, within the GBM microenvironment. Our work provides insights into glutamate release dynamics, representing its importance for GBM growth, viability, and migration. Based on newly published multi-omic datasets, we explored the and characterized the functions of different ionotropic and metabotropic glutamate receptors, of which the metabotropic receptor 3 (GRM3) is highlighted through its modulatory role in maintaining the ability of GBM cells to evade standard alkylating chemotherapeutics. We addressed the clinical relevance of GRM3 receptor expression in GBM and provide a proof of concept where we manipulate intrinsic mechanisms of chemoresistance, driving GBM towards chemo-sensitization through GRM3 receptor inhibition. Finally, we validated our findings in our novel human organotypic section-based tumor model, where GBM growth and proliferation was significantly reduced when GRM3 inhibition was combined with temozolomide application. Our findings present a new picture of how glutamate signaling via mGluR3 interacts with the phenotypical GBM transcriptional programs in light of recently published GBM cell-state discoveries.
胶质母细胞瘤（GBM）是中枢神经系统最恶性的肿瘤，其特征是对微环境龛位的动态反应。特别是，这种细胞可塑性有助于在肿瘤治疗过程中立即产生耐药性。对 GBM 表现出的发育轨迹的新认识表明，它具有通过特定表型的克隆选择来响应其微环境的强大能力。恶性 GBM 利用相同的机制发展内在的机制来抵抗化疗。据报道，这种耐药性通过离子型和代谢型谷氨酸受体的旁分泌和自分泌谷氨酸信号持续存在。然而，谷氨酸能信号在多大程度上调节 GBM 的化疗耐药性和转录谱仍未被探索。在这项研究中，我们旨在绘制谷氨酸信号在 GBM 中的多方面影响图谱，作为进一步发现特定受体在 GBM 微环境中的调节作用和相互作用的基础。我们的工作深入了解了谷氨酸释放动力学，这对 GBM 的生长、活力和迁移具有重要意义。基于新发表的多组学数据集，我们探索并表征了不同离子型和代谢型谷氨酸受体的功能，其中代谢型谷氨酸受体 3（GRM3）因其在维持 GBM 细胞逃避标准烷化化疗药物能力方面的调节作用而被突出强调。我们研究了 GRM3 受体在 GBM 中的临床相关性，并提供了一个概念验证，即通过抑制 GRM3 受体来操纵内在的化疗耐药机制，从而使 GBM 向化疗敏感化方向发展。最后，我们在我们的新型基于人器官样切片的肿瘤模型中验证了我们的发现，当 GRM3 抑制与替莫唑胺联合应用时，GBM 的生长和增殖明显减少。我们的研究结果呈现了一个新的图景，即谷氨酸能信号通过 mGluR3 与最近发表的 GBM 细胞状态发现中的表型 GBM 转录程序相互作用。
