DAP5-dependent translational control and breast cancer metastasis

DAP5依赖的翻译控制和乳腺癌转移

基本信息

批准号：
10577813
负责人：
Robert Schneider
金额：
$ 50.48万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-02 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577813
关键词：
3&apos Untranslated Regions 5&apos Untranslated Regions Aftercare Animal Model Apoptosis Applications Grants Automobile Driving Binding Binding Sites Biopsy Blood Vessels Breast Cancer Model Breast Cancer cell line Breast cancer metastasis Cancer Control Cell Line Cells Complex Data Development Extravasation Homologous Gene Human Immune Impairment Invaded Knockout Mice Malignant Neoplasms Mammary Neoplasms Mediating Messenger RNA Methylation Modeling Modification Mus Neoplasm Metastasis Oncogenic Paraffin Embedding Pathway interactions Patients Peptide Initiation Factors Phenotype Prevention Primary Neoplasm Proteins Recurrence Research Role Site Testing Tissues Translating Translation Initiation Translational Regulation Translations Xenograft procedure cancer cell conditional knockout epithelial to mesenchymal transition genome-wide in vivo mRNA Translation malignant breast neoplasm member migration molecular marker neoplastic cell patient derived xenograft model power analysis targeted biomarker transcriptomics triple-negative invasive breast carcinoma tumor tumor initiation tumor progression

项目摘要

Cancer development, tumor formation, progression, invasion and metastasis all involve selective mRNA translation but much of the understanding by which oncogenic translation occurs remains to be characterized. We recently discovered a new mechanism of cap-dependent mRNA translation that established a new paradigm for translational regulation, in that it is cap-dependent but does not involve the canonical pre-initiation machinery. We showed that the canonical eIF4E/eIF4GIfactors are not required for approximately 20% of mRNAs that use the translation initiation complex known as DAP5/eIF3d, which utilizes the cap binding activity of translation initiation factor eIF3d rather than eIF4E and eIF4GI homolog, DAP5. We found that DAP5/eIF3d is essential for breast cancer metastasis in animal models and strongly associated with human breast cancer metastasis. Here we propose to study the role of DAP5/eIF3d-mediated mRNA translation in breast cancer development and metastasis. We will determine the roles of DAP5/eIF3d-mediated mRNA translation in tumor development, invasion and metastasis, using syngeneic mouse mammary cancer models, human xenotransplant breast cancer cell line models and a heterogeneous patient derived xenograft model, the latter two models carried out in immune impaired mice. We will characterize the requirement for DAP5/eIF3d versus eIF4GI/eIF4E initiation of translation on cancer cell epithelial to mesenchymal transition (EMT), stromal tissue invasion, vascular intravasation, extravasation, migration, prevention of apoptosis resulting from cell detachment and migration, and colonization. Other studies will characterize by genome-wide trancriptomic and translatomic analyses the mRNAs selectively translated by DAP5/eIF3d and required for progression to metastasis, compared to mRNAs translated by eIF4E/eIF4GI in animal models. These studies will further our understanding of the role of DAP5- selective mRNA translation in driving specific oncogenic pathways involved in metastatic tumor progression. We will also test the importance of specific DAP5 mRNA translation targets in DAP5-mediated metastatic tumor progression. Finally, studies will be carried out to understand the mechanism(s) for DAP5/eIF3d-mediated selective mRNA translation. Studies will focus on the role of a specific form of mRNA modification by methylation known as m6A because we have found strong preliminary data in support of its importance.

癌症发展，肿瘤形成，进展，侵袭和转移都涉及选择性mRNA 翻译，但发生致癌翻译的许多理解尚待表征。我们最近发现了一种新的依赖帽的mRNA翻译机制，该机制建立了一个新的范式对于翻译调节，它是依赖帽的，但不涉及规范的预先发射机制。我们表明，大约20％的使用mRNA不需要规范的EIF4E/EIF4GIFACTORS 翻译起始复合物称为DAP5/EIF3D，它利用翻译的盖结合活性启动因子EIF3D而不是EIF4E和EIF4GI同源物DAP5。我们发现DAP5/EIF3D对于动物模型中的乳腺癌转移，与人类乳腺癌转移密切相关。这里我们建议研究DAP5/EIF3D介导的mRNA翻译在乳腺癌发育和转移。我们将确定DAP5/EIF3D介导的mRNA翻译在肿瘤发育中的作用，侵袭和转移，使用同性小鼠乳腺癌模型，人类自武植物乳房癌细胞系模型和异质性患者衍生的异种移植模型，后两个模型进行了在免疫受损的小鼠中。我们将表征DAP5/EIF3D与EIF4GI/EIF4E启动的要求癌细胞上皮上的翻译向间质转变（EMT），基质组织侵袭，血管侵入，渗出，迁移，预防细胞脱离和迁移引起的凋亡，和殖民化。其他研究将以全基因组trancriptomic和Translatomic分析来表征与mRNA相比由EIF4E/EIF4GI翻译在动物模型中。这些研究将进一步了解DAP5-的作用选择性mRNA翻译驱动参与转移性肿瘤进展的特定致癌途径。我们还将测试DAP5介导的转移性肿瘤中特定DAP5 mRNA翻译靶标的重要性进展。最后，将进行研究以了解DAP5/EIF3D介导的机制选择性mRNA翻译。研究将侧重于通过甲基化特定形式的mRNA修饰形式的作用之所以被称为M6A，是因为我们发现了强大的初步数据以支持其重要性。