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

rRNA 和 mRNA m6A 轴对间质转化的翻译调节

• 批准号: 10630936
• 负责人: Clara Theresa Vincent
• 金额: $ 41.74万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630936
• 关键词: Aftercare; Animal Model; Applications Grants; Binding; Binding Sites; Biogenesis; Biopsy; Blood Vessels; Breast Cancer Cell; Breast Cancer cell line; Breast cancer metastasis; Cells; ChIP-seq; Chemoresistance; Clinical Treatment; Complex; DNA Polymerase I; DNA Polymerase II; Data; Development; Disease; Disease Progression; Distant; Drug Targeting; Epithelial Cells; Epithelium; G1 Phase; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic Transcription; Human; Investigation; Knowledge; Link; Mass Spectrum Analysis; Mediating; Mesenchymal; Messenger RNA; Metastatic breast cancer; Methyltransferase; Modification; Molecular; Mus; Neoplasm Metastasis; Nuclear; Organ; Paraffin Embedding; Patients; Peptide Initiation Factors; Physiological; Play; Positioning Attribute; Primary Neoplasm; Process; Property; RNA Polymerase I; Recurrence; Regulator Genes; Research; Ribosomal DNA; Ribosomal RNA; Ribosomes; Role; Signal Transduction; Snails; Stimulus; Therapeutic; Transcriptional Regulation; Transforming Growth Factor beta; Translating; Translational Regulation; Translations; cancer cell; cell motility; effective therapy; epithelial to mesenchymal transition; genome-wide; infectious disease treatment; mRNA Translation; malignant breast neoplasm; manufacture; methylome; molecular marker; neoplastic cell; novel; novel therapeutics; overexpression; power analysis; prevent; programs; recruit; therapeutic target; transcription factor; triple-negative invasive breast carcinoma; tumor; tumor progression; vector

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.

项目摘要 目前还没有有效的治疗方法可以治愈转移性乳腺癌。上皮细胞- 间充质转化（EMT）是一种关键的癌细胞可塑性和去分化程序， 细胞获得促迁移和侵入间充质性质。为了启动EMT项目，癌细胞 需要接收pro-EMT信号，例如来自邻近肿瘤细胞或来自肿瘤细胞的TGF β 1。 微环境（周围基质）。 本课题组在TGFβ介导的EMT过程中意外发现， 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， 细胞侵袭性和转移性扩散所需的依赖性基因表达程序;（2）同时 Myc的缺失发生在rDNA基因上;（3）Snail与胃L5形成复合物，使新产生的 rRNA在掺入成熟核糖体之前被胃L5修饰为m6 A;（4）Snail也 与胃L3形成复合物，因此可以指导选择性mRNA的m6 A修饰;（5）m6 A 标记的mRNA能够募集非经典的DAP 5/eIF 3d/胃L3翻译复合物， 间充质状态下选择性m6 A标记的mRNA翻译;和（6）需要胃L5来执行 EMT程序，因为胃L5的沉默阻止细胞经历EMT。 本次资助申请的重点是获得对Pol I rDNA更深入的分子理解 转录，胃L5 m6 A修饰的rRNA和核糖体以及为什么选择性DAP 5/eIF 3d介导 翻译控制对于协调EMT中乳腺癌细胞的可塑性至关重要，其在乳腺癌中的作用 癌症转移进展，以及Snail如何协调和协调m6 A rRNA/mRNA轴。 这些知识将最终告知如何靶向Pol I机器，专门的核糖体和翻译 对照可能代表一种新的治疗方法，专门针对塑料，非增殖和化学抗性 EMT细胞促进肿瘤复发和转移。