Extracellular vesicle RNA as systemic modulators of the tumor microenvironment in B cell lymphoma

细胞外囊泡 RNA 作为 B 细胞淋巴瘤肿瘤微环境的系统调节剂

基本信息

批准号：
345462466
负责人：
Dr. Florian Kuchenbauer
金额：
--
依托单位：
BC Cancer Research Centre
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/345462466?language=en
关键词：
Extracellular vesicle RNA systemic modulators

项目摘要

Extracellular vesicles (EVs) are important mediators of intercellular communication and are involved in many physiological processes. They are present in almost any fluid compartment of our bodies and can be detected even at distant sites of their cell of origin. Within the last decade, their critical involvement in cancer development, progression and dissemination has become more and more obvious. EVs consist of a lipid bilayer membrane displaying cell surface proteins of their cell of origin and contain mainly protein and RNA molecules. It is now clear that EVs can interact with cells via their surface molecules and can transfer their content to target cells. The transferred material, e.g. proteins, messengerRNAs or microRNAs, was shown to be active in recipient cells, leading to changes in their phenotypes. Under physiological conditions, EVs act as mediators of immune responses, and there are indications that tumor-derived EVs contribute to disease-associated inflammation and immune suppression.Tumor cell-derived EVs have so far been mainly studied in solid cancers, and there is only little data on EVs produced by malignant cells in hematological diseases. Therefore, the aim of our proposed project is an extensive analysis of EVs, with a focus on exosomes, derived from malignant cells of chronic lymphocytic leukemia (CLL), multiple myeloma (MM) and diffuse large B cell lymphoma (DLBCL). The study includes i) comparative proteome and RNA analyses of exosomes, with a focus on Y RNAs and microRNAs and their sorting mechanisms; ii) the identification of target cells within the hematopoietic microenvironment that take up tumor-derived exosomes in vitro and in mouse models; iii) a characterization of downstream changes within the transcriptome, secretome and signaling capacities of target cells, focusing hereby on inflammatory responses that are mediated by toll-like receptors; as well as iv) investigations to evaluate the impact of exosomes on B cell lymphoma development in suitable mouse models. Finally, we will v) investigate in a translational approach the potential of exosomes as biomarkers and as therapeutic target in preclinical studies in mice.

细胞外囊泡（EV）是细胞间通信的重要介体，参与了许多生理过程。它们几乎存在于我们身体的任何液体室中，即使在其原始细胞的远处也可以检测到。在过去的十年中，它们在癌症发展，进展和传播中的关键参与变得越来越明显。电动汽车由脂质双层膜组成，该膜显示其原产细胞的细胞表面蛋白，主要包含蛋白质和RNA分子。现在很明显，电动汽车可以通过其表面分子与细胞相互作用，并可以将其含量转移到靶细胞上。转移的材料，例如蛋白质，梅尔纳斯或microRNA被证明在受体细胞中活跃，导致其表型变化。在生理条件下，电动汽车充当免疫反应的介体，并且有迹象表明肿瘤衍生的电动汽车有助于与疾病相关的炎症和免疫抑制。到目前为止，主要在固体癌症中研究了细胞衍生的EV，仅在血液学性疾病中的恶性细胞对EVS产生的数据很少。因此，我们提出的项目的目的是对电动汽车的广泛分析，重点是外泌体，这些外泌体来自慢性淋巴细胞性白血病（CLL），多发性骨髓瘤（MM）和弥漫性大B细胞淋巴瘤（DLBCL）的恶性细胞（DLBCL）。该研究包括i）外泌体的比较蛋白质组和RNA分析，重点是Y RNA和microRNA及其分类机制； ii）在造血微环境中鉴定靶细胞在体外和小鼠模型中占据肿瘤衍生的外泌体； iii）靶细胞转录组，分泌组和信号能力内下游变化的表征，在此集中在炎症反应上，这些反应是由Toll样受体介导的；以及IV）研究，以评估外泌体对合适小鼠模型中B细胞淋巴瘤发育的影响。最后，我们将v）在翻译方法中调查外泌体作为生物标志物的潜力和小鼠临床前研究中的治疗靶标。