exRNA in colorectal carcinoma: biogenesis and function

总结-整体组件 现在认识到不同细胞之间的细胞通讯严重影响癌症的发生和发展。 进展最近，几种新形式的细胞间通讯已被确认，包括 通过细胞外囊泡（EV）和其他载体交换蛋白质和RNA。细胞外RNA（ExRNA） 是特别有趣的，因为它有可能影响基因表达和潜在的表观遗传状态。 特别是微RNA（miRNAs）已经被证明可以从一种细胞类型转移到另一种细胞类型， 影响基因表达;然而，很明显，许多种类的exRNA选择性地从细胞分泌。 不太清楚的是这些exRNA（包括miRNA）是如何包装到EV和其他载体中的。在 此外，这些exRNA对细胞和组织的总体影响尚未被理解。在这个项目中，我们 建议阐明细胞外RNA通讯的“游戏规则”，使用结直肠癌 (CRC)作为一个模型系统。我们的计划将高度协同，因为每个项目侧重于不同的 这个问题的一个方面。因此，项目1将确定细胞器之间的亚细胞接触如何驱动RNA 和RNA结合蛋白（RBP）转移到CRC中的EV。项目2将识别RNA修饰， 这些序列驱动RNA的分子选择以转移到CRC中的EV中。项目3将确定电动汽车如何 外泌体介导CRC中的EGFR-Wnt串扰。所有项目均使用通用实验系统，包括 CRC同基因细胞模型，并且具有共同的生物学焦点（例如，miR-100和miR-125 b如何被运输 并影响CRC中的受体细胞功能）。项目的整合、协同和进展将得到高度重视。 在拟议的行政和共享资源核心的推动下，该计划将使 在CRC、肿瘤微环境、exRNA、EV和RNA生物学领域产生重大影响。

Summary – Overall Component Cellular communication between diverse cells is now recognized to heavily influence both cancer initiation and progression. Recently, several new forms of intercellular communication have been recognized, including exchange of proteins and RNAs via extracellular vesicles (EVs) and other carriers. Extracellular RNA (ExRNA) is particularly interesting, as it has the potential to influence gene expression and potentially epigenetic states. MicroRNAs (miRNAs) in particular have been shown to be transferred from one cell type to another to influence gene expression; however, it is clear that many kinds of exRNAs are selectively secreted from cells. What is less clear is how those exRNAs (including miRNAs) are packaged into EVs and other carriers. In addition, the overall impact of these exRNAs on cells and tissues is not yet understood. In this program, we propose to elucidate the “rules of the game” for extracellular RNA communication, using colorectal carcinoma (CRC) as a model system. Our Program will be highly synergistic, because each Project focuses on a different aspect of this problem. Thus, Project 1 will determine how subcellular contacts between organelles drive RNA and RNA-binding protein (RBP) transfer to EVs in CRC. Project 2 will identify RNA modifications and sequences that drive molecular selection of RNAs for transfer into EVs in CRC. Project 3 will identify how EVs and exomeres mediate EGFR-Wnt crosstalk in CRC. All Projects use common experimental systems, including CRC isogenic cell models, and have common biological focus (e.g. how miR-100 and miR-125b are trafficked and influence recipient cell function in CRC). Integration, synergy, and progress of the Projects will be highly enhanced by the proposed Administrative and Shared Resource Cores. Together this Program will make a major impact in the areas of CRC, tumor microenvironment, exRNA, EVs, and RNA biology.