Extracellular vesicles as biomarkers in gliomas and their role in tumor progression

细胞外囊泡作为神经胶质瘤的生物标志物及其在肿瘤进展中的作用

• 批准号: 422037109
• 负责人: Privatdozent Dr. Franz Ricklefs
• 金额: --
• 依托单位: Klinik und Poliklinik für Neurochirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/422037109?language=en
• 关键词: Extracellular; vesicles; biomarkers; gliomas; their

Exosomes and microvesicles are extracellular vesicles (EVs) that are involved in the communication between different tumor cells and also between tumor cells and host cells. EVs contain RNA, DNA and protein, and the uptake of tumor cell-derived EVs (tEVs) can manipulate the phenotype of recipient cells. In glioblastomas, which represent the most frequent type of malignant brain tumors, tEVs contribute to oncogenic signaling, angiogenesis, immunosuppression and treatment resistance. tEVs are further released into the blood circulation, where molecules inside EVs are protected from degradation, rendering circulating EVs a potentially valuable biomarker source to monitor tumor evolution and treatment response. Our project pursues two major goals. First, we aim to perform an in-depth analysis of the molecular cargo contained in glioma EVs, in order to assess whether the complex mutational, epigenetic, transcriptional and proteomic profile of the original tumor is reflected in the tEVs. Our preliminary work revealed that the number of circulating EVs is elevated in the plasma of glioblastoma patients and we aim to trace both EV counts as well as tumor-specific genetic alterations in circulating EVs longitudinally in glioma patients, in order to determine whether EVs obtained by liquid biopsy allow dynamic monitoring of the tumor state and response to therapy. Second, we aim to map the dissemination of glioma-derived EVs throughout the body in immunocompetent and immunodeficient mouse models. Preliminary work from our group showed that purified glioma cell-derived EVs injected into the mouse brain parenchyma accumulate in deep cervical lymph nodes. We will investigate whether these EVs are transported through the meningeal lymphatic and glymphatic system and/or via hematogenous pathways and whether tEVs accumulate also in peripheral organs. Further, we will assess the effect of the immune system on EV dissemination and examine whether the uptake of glioma-derived EVs by microglia and macrophages reprograms these cells toward a more immunosuppressive phenotype in vivo. Collectively, these studies will show whether glioma EVs can be used as a biomarker source to obtain diagnostic information and examining disease progression and whether EVs are distributed through lymphatic pathways and contribute to tumor-induced immunosuppression in vivo.

外来体和微泡是参与不同肿瘤细胞之间以及肿瘤细胞与宿主细胞之间的通讯的细胞外囊泡（EV）。EV含有RNA、DNA和蛋白质，并且肿瘤细胞衍生的EV（tEV）的摄取可以操纵受体细胞的表型。在代表最常见类型的恶性脑肿瘤的胶质母细胞瘤中，tEV有助于致癌信号传导、血管生成、免疫抑制和治疗抗性。tEV进一步释放到血液循环中，其中EV内的分子被保护免于降解，使得循环EV成为监测肿瘤演变和治疗反应的潜在有价值的生物标志物来源。我们的项目追求两个主要目标。首先，我们的目标是对胶质瘤EV中包含的分子货物进行深入分析，以评估原始肿瘤的复杂突变，表观遗传，转录和蛋白质组学特征是否反映在tEV中。我们的初步工作显示，胶质母细胞瘤患者血浆中循环EV的数量升高，我们的目标是纵向追踪胶质瘤患者循环EV中的EV计数以及肿瘤特异性遗传改变，以确定通过液体活检获得的EV是否允许动态监测肿瘤状态和对治疗的反应。第二，我们的目标是在免疫活性和免疫缺陷小鼠模型中绘制神经胶质瘤源性EV在全身的传播。我们小组的初步工作表明，注射到小鼠脑实质中的纯化的胶质瘤细胞衍生的EV在颈深淋巴结中积累。我们将研究这些EV是否通过脑膜淋巴和胶质淋巴系统和/或通过造血途径转运，以及tEV是否也在外周器官中积累。此外，我们将评估免疫系统对EV传播的影响，并检查小胶质细胞和巨噬细胞对胶质瘤源性EV的摄取是否将这些细胞重新编程为体内更具免疫抑制性的表型。总的来说，这些研究将显示胶质瘤EV是否可以用作生物标志物来源以获得诊断信息和检查疾病进展，以及EV是否通过淋巴途径分布并有助于体内肿瘤诱导的免疫抑制。