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
基本信息
- 批准号:10630936
- 负责人:
- 金额:$ 41.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AftercareAnimal ModelApplications GrantsBindingBinding SitesBiogenesisBiopsyBlood VesselsBreast Cancer CellBreast Cancer cell lineBreast cancer metastasisCellsChIP-seqChemoresistanceClinical TreatmentComplexDNA Polymerase IDNA Polymerase IIDataDevelopmentDiseaseDisease ProgressionDistantDrug TargetingEpithelial CellsEpitheliumG1 PhaseGene ExpressionGene Expression RegulationGenerationsGenesGenetic TranscriptionHumanInvestigationKnowledgeLinkMass Spectrum AnalysisMediatingMesenchymalMessenger RNAMetastatic breast cancerMethyltransferaseModificationMolecularMusNeoplasm MetastasisNuclearOrganParaffin EmbeddingPatientsPeptide Initiation FactorsPhysiologicalPlayPositioning AttributePrimary NeoplasmProcessPropertyRNA Polymerase IRecurrenceRegulator GenesResearchRibosomal DNARibosomal RNARibosomesRoleSignal TransductionSnailsStimulusTherapeuticTranscriptional RegulationTransforming Growth Factor betaTranslatingTranslational RegulationTranslationscancer cellcell motilityeffective therapyepithelial to mesenchymal transitiongenome-wideinfectious disease treatmentmRNA Translationmalignant breast neoplasmmanufacturemethylomemolecular markerneoplastic cellnovelnovel therapeuticsoverexpressionpower analysispreventprogramsrecruittherapeutic targettranscription factortriple-negative invasive breast carcinomatumortumor progressionvector
项目摘要
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.
项目概要
目前尚无有效的治疗方法可以治愈转移性乳腺癌。
间质转化(EMT)是一种关键的癌细胞可塑性和去分化程序,通过该程序,上皮细胞
细胞获得促迁移和侵袭性间质特性,以启动 EMT 程序,癌细胞。
需要接收促 EMT 信号,例如来自邻近肿瘤细胞或来自肿瘤细胞的 TGF
微环境(基质周围)。
我们的研究小组意外地发现,在TGFβ介导的EMT过程中,Pol I 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
(2)细胞侵袭和转移扩散所需的并发依赖性基因表达程序;
Myc 的丢失发生在 rDNA 基因上;(3) Snail 与 METTL5 形成复合物,使新产生的
rRNA在整合到成熟核糖体之前是通过METTL5进行m6A修饰的(4)Snail也;
与 METTL3 形成复合物,因此可以指导选择性 mRNA 的 m6A 修饰 (5) m6A;
标记的 mRNA 能够招募非规范的 DAP5/eIF3d/METTL3 翻译复合物来驱动
间充质状态下选择性 m6A 标记的 mRNA 翻译;以及 (6) METTL5 是执行过程所必需的;
EMT 程序,因为 METTL5 的沉默会阻止细胞进行 EMT。
本次资助申请的重点是获得对 Pol I rDNA 更深入的分子了解
转录、METTL5 m6A 修饰的 rRNA 和核糖体以及为什么选择性 DAP5/eIF3d 介导
翻译控制对于在 EMT 中协调乳腺癌细胞可塑性至关重要,其在乳腺癌中的作用
癌症转移进展,以及 Snail 如何编排和协调 m6A rRNA/mRNA 轴。
这些知识最终将告诉我们如何靶向 Pol I 机器、专门的核糖体和翻译
控制可能代表一种专门针对塑料、不增殖和化疗耐药的新疗法
EMT 细胞促进肿瘤复发和转移。
项目成果
期刊论文数量(0)
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