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：
10349506
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/10349506
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 Genetic Translation Homologous Gene Human Immune Impairment 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 Research Role Site Testing Tissues Translating Translation Initiation Translational Regulation Translations base cancer cell conditional knockout epithelial to mesenchymal transition genome-wide in vivo 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.

癌症的发生、肿瘤形成、进展、侵袭和转移都涉及选择性mRNA 但对致癌翻译发生的许多理解仍有待表征。我们最近发现了一种帽依赖性 mRNA 翻译的新机制，建立了新的范例对于翻译调节，因为它依赖于上限，但不涉及规范的预启动机制。我们发现大约 20% 的 mRNA 不需要规范的 eIF4E/eIF4GI 因子称为 DAP5/eIF3d 的翻译起始复合物，它利用翻译的帽子结合活性起始因子 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 翻译在乳腺癌发生和发展中的作用转移。我们将确定 DAP5/eIF3d 介导的 mRNA 翻译在肿瘤发展中的作用，侵袭和转移，使用同基因小鼠乳腺癌模型，人类异种移植乳房癌细胞系模型和异质患者衍生的异种移植模型，后两种模型进行在免疫受损的小鼠中。我们将描述 DAP5/eIF3d 与 eIF4GI/eIF4E 启动的要求癌细胞上皮间质转化（EMT）、基质组织侵袭、血管的翻译内渗、外渗、迁移、防止细胞脱离和迁移导致的细胞凋亡，和殖民。其他研究将通过全基因组转录组学和翻译组学分析来表征与 mRNA 相比，由 DAP5/eIF3d 选择性翻译的 mRNA 是进展至转移所需的在动物模型中由 eIF4E/eIF4GI 翻译。这些研究将进一步我们对 DAP5- 作用的理解选择性 mRNA 翻译驱动参与转移性肿瘤进展的特定致癌途径。我们还将测试特定 DAP5 mRNA 翻译靶点在 DAP5 介导的转移性肿瘤中的重要性进展。最后，将进行研究以了解 DAP5/eIF3d 介导的机制选择性 mRNA 翻译。研究将集中于甲基化修饰特定形式的 mRNA 的作用称为 m6A，因为我们发现了强有力的初步数据来支持其重要性。