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

外泌体和微囊泡是细胞外囊泡（ev），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。ev含有RNA、DNA和蛋白质，对肿瘤细胞源性ev （tEVs）的摄取可以操纵受体细胞的表型。在恶性脑肿瘤中最常见的胶质母细胞瘤中，tev参与致瘤信号、血管生成、免疫抑制和治疗抵抗。tev进一步释放到血液循环中，在血液循环中，ev内的分子被保护不被降解，使循环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。我们的项目有两个主要目标。首先，我们的目标是对胶质瘤ev中所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。我们的初步研究表明，胶质母细胞瘤患者血浆中循环EV的数量升高，我们的目标是追踪胶质母细胞瘤患者血浆中循环EV的数量以及肿瘤特异性基因改变，以确定液体活检获得的EV是否可以动态监测肿瘤状态和对治疗的反应。其次，我们的目标是在免疫正常和免疫缺陷小鼠模型中绘制胶质瘤来源的ev在全身的传播图。我们小组的初步工作表明，纯化的胶质瘤细胞衍生的ev注射到小鼠脑实质中，在颈深部淋巴结中积累。我们将研究这些ev是否通过脑膜淋巴和淋巴系统和/或通过血液途径运输，以及tev是否也在周围器官积累。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来源EV的摄取是否会使这些细胞在体内重新编程，使其更具免疫抑制表型。总的来说，这些研究将表明胶质瘤EVs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EVs是否通过淋巴通路分布并有助于肿瘤诱导的体内免疫抑制。

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.