Translation regulation of the mesenchymal transition by the rRNA and mRNA m6A axis

项目总结 目前还没有有效的治疗方法可以治愈转移性乳腺癌。上皮到- 间充质转化(EMT)是一种重要的癌细胞可塑性和去分化程序，通过它，上皮细胞 细胞获得亲迁移和侵袭性间充质特性。为了启动EMT计划，癌细胞 需要接收促EMT信号，例如来自邻近肿瘤细胞或来自 微环境(基质周围)。 我们的研究小组有了一个意想不到的发现，在转化生长因子β介导的EMT过程中，Poli rDNA转录 是：(1)由Snail驱动，Snail是一种已知在协调间充质Pol II中发挥核心作用的转录因子 细胞侵袭和转移扩散所需的依赖基因表达程序；(2)并发 Myc的丢失发生在rDNA基因上；以及(3)Snail与METTL5形成复合体，使新制造的 RRNA是在rRNA进入成熟核糖体之前被METTL5修饰的m6A；(4)Snail也 与METTL3形成复合体，因此可以指导选择性mRNA的m6A修饰；(5)m6A 标记的mRNAs使非规范的DAP5/eIF3d/METTL3翻译复合体的招募能够推动 间充质状态下选择性m6A标记的mRNA翻译；以及(6)需要METTL5来执行 EMT程序，因为沉默的METTL5阻止细胞进行EMT。 这项资助申请的重点是加深对Poli rDNA的分子理解 转录，METTL5 m6A修饰rRNA和核糖体以及为什么选择性DAP5/eIF3d介导 在EMT中，翻译控制对于协调乳腺癌细胞的可塑性及其在乳腺中的作用是必不可少的 癌症转移进展，以及Snail如何协调和协调m6A rRNA/mRNA轴。 这一知识最终将告诉我们如何靶向Pol I机制、专门的核糖体和翻译 CONTROL可能代表了一种专门针对塑料、非增殖性和耐化疗的新疗法 EMT细胞促进肿瘤复发和转移。

PROJECT SUMMARY Currently there are no effective treatments that can cure metastatic breast cancer. The epithelial-to- mesenchymal transition (EMT) is a critical cancer cell plasticity and dedifferentiation program by which epithelial cells acquire pro-migratory and invasive mesenchymal properties. To initiate the EMT program, cancer cells need to receive pro-EMT signals, such as TGF from either neighboring tumor cells or from the microenvironment (surrounding stroma). Our research group made the unexpected finding that during TGFβ mediated EMT, Pol I rDNA transcription is: (1) driven by Snail, a transcription factor known to play a central role in orchestrating the mesenchymal Pol II dependent gene expression program required for cellular invasiveness and metastatic spread; (2) a concurrent loss of Myc occurs at rDNA genes; and (3) Snail forms a complex with METTL5 to enable that the newly made rRNA are m6A modified by METTL5 before the rRNA is incorporated into the mature ribosome; (4) Snail also forms a complex with METTL3 and may therefore direct m6A modifications of selective mRNAs; (5) the m6A marked mRNAs enables recruitment of the non-canonical DAP5/eIF3d/METTL3 translation complex to drive selective m6A marked mRNA translation in the mesenchymal state; and (6) METTL5 is required for execution of the EMT program, as silencing of METTL5 prevents cells from undergoing EMT. The focus of this grant application is to gain a deeper molecular understanding of Pol I rDNA transcription, METTL5 m6A modified rRNA and ribosomes and why selective DAP5/eIF3d mediated translational control is essential for orchestrating breast cancer cell plasticity in EMT, its role in breast cancer metastatic progression, and how Snail orchestrates and coordinates the m6A rRNA/mRNA axis. This knowledge will ultimately inform how targeting Pol I machinery, specialized ribosomes and translation control could represent a novel therapy specifically targeting the plastic, non-proliferating and chemo-resistant EMT cells fueling tumor reoccurrence and metastasis.