Transfer of microRNA regulators from glioblastoma to brain microenvironment

项目负责人：安娜克里切夫斯基。胶质母细胞瘤（GBM）是成人中最常见的恶性脑肿瘤，也占 大约10%的儿童中枢神经系统肿瘤。尽管有非常积极的疾病管理， 包括手术，化疗和放疗，GBM是一种致命的疾病，中位生存时间仅为 12-15个月。因此，迫切需要针对GBM的新方法和分子靶点。 微RNA（miRNAs）的发现，小的调节RNA分子，引起转录后 基因表达下调，真正彻底改变了癌症生物学领域。它提出了一个完全 新的基因调控层，可能参与人类肿瘤的进展和维持。 我们在过去8年的工作集中在有助于胶质瘤形成的miRNAs上，今天我们已经 越来越多的证据表明GBM的生长和侵袭性受到miRNA的密切调控。 重要的是，由GBM释放的微囊泡（其可以代表微囊泡之间的通信手段）可以被称为微囊泡。 肿瘤及其颅内环境），含有大量的miRNA调节剂，包括关键的 致癌miRNAs。我们假设这些分子被周围的正常细胞吸收， 肿瘤，并对这些细胞的生理学有显着影响。MicroRNA介导的基因调控 受体细胞中的表达可能导致脑细胞中的转化事件， 或最终的肿瘤生长支持功能。为了验证这一假设，我们将：1）描述 人和小鼠GBM细胞中细胞内相对于细胞外/释放的RNA的库，和 构成GBM微环境的正常脑细胞中的细胞内RNA; 2）研究miRNA转移 GBM和正常细胞在体外共培养中的作用，及其对GBM表型的功能影响。 受体细胞，和3）研究在异种移植GBM模型之间是否存在miRNA转移， 在动物体内的正常脑细胞。拟议的工作有望产生重大的新见解， 神经胶质瘤的生物学和更普遍的-miRNA介导的不同细胞群之间的串扰， 个脑袋

Prject Leader: Anna Krichevsky. Glioblastoma (GBM) is the most common and malignant brain tumor in adults and also accounts for approximately 10% of pediatric CNS tumors. Despite very aggressive disease management, that usually includes surgery, chemotherapy and radiotherapy, GBM is a fatal disease with median survival time of only 12-15 months. Novel approaches and molecular targets for GBM are, therefore, urgently needed. The discovery of microRNAs (miRNAs), small regulatory RNA molecules that cause post-transcriptional down-regulation of gene expression, truly revolutionized the field of cancer biology. It suggested an entirely new layer of gene regulation that might be involved in progression and maintenance of human neoplasia. Our work over the past 8 years focused on miRNAs that contribute to gliomagenesis, and today we have mounting evidence indicating that GBM growth and invasiveness are closely regulated by miRNAs. Importantly, microvesicles released by GBM (which may represent a means of communication between the tumor and its intracranial environment), contain large amounts of miRNA regulators, including the key oncogenic miRNAs. We hypothesize that these molecules are taken-up by normal cells surrounding the tumor, and have significant effects on the physiology of these cells. MicroRNA-mediated regulation of gene expression in the recipient cells may lead to transformative events in the brain cells, serving either protective or, ultimately, tumor growth-supportive function. To validate this hypothesis, we will: 1) characterize the repertoire of intracellular versus extracellular/released RNA in human and mouse GBM cells, and intracellular RNA in normal brain cells that constitute GBM microenvironment; 2) investigate miRNA transfer between GBM and normal cells in co-cultures in vitro, and its functional effects on the phenotypes ofthe recipient cells, and 3) investigate whether miRNA transfer exists between the xenograft GBM models and normal brain cells in animals in vivo. The proposed work promises to yield significant new insights into the biology of glioma and more generally- miRNA-mediated crosstalk between different cell populations in the brain.