Elucidating the role of RNA splicing in the metastatic seeding and outgrowth of aggressive cancers.

阐明 RNA 剪接在侵袭性癌症的转移播种和生长中的作用。

基本信息

批准号：
10665061
负责人：
Kimberly Parker
金额：
$ 4.32万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
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：
2022-07-13 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10665061
关键词：
Address Affect Alternative Splicing Automobile Driving Binding Bioinformatics Biology Breast Breast Cancer Cell Breast cancer metastasis Cancer Etiology Cell Survival Cells Cessation of life Clinical Clinical Research Coiled-Coil Domain Complex Data Development Disease Disseminated Malignant Neoplasm Distal Epigenetic Process Event Fibroblasts Foundations Future Genes Genetic Goals Grant Heterogeneity Immune Evasion Immunologic Surveillance In Vitro Individual Integrins International Invaded Investigation Learning Ligase Malignant Neoplasms Mediating Mentors Mentorship Metastatic breast cancer Methods Molecular Neoplasm Metastasis Organ Paper Patient-Focused Outcomes Phase Phenotype Play Population Postdoctoral Fellow Primary Neoplasm Process Proliferating Protein Isoforms Proteins RNA RNA Processing RNA Splicing RNA-targeting therapy Regulation Relapse Research Research Activity Research Institute Research Project Grants Research Proposals Role Scientist Signal Transduction Site T-Lymphocyte Techniques Therapeutic Tissues Transcript United States Untranslated RNA Validation Variant Work Writing angiogenesis cancer cell cancer stem cell career crosslinking and immunoprecipitation sequencing improved in vivo malignant breast neoplasm meetings neoplastic cell novel novel therapeutic intervention overexpression post-doctoral training potential biomarker pre-doctoral preclinical study programs response self-renewal skills stem cell biomarkers student mentoring symposium targeted treatment therapeutic target tool transcriptome sequencing transcriptomics triple-negative invasive breast carcinoma tumor growth tumor initiation tumor microenvironment tumorigenic

项目摘要

Project Summary/Abstract Metastasis is the process in which disseminated tumor cells (DTCs) spread to distal tissues and organs, and it is the leading cause of cancer-related deaths. In order to complete the metastatic cascade, DTCs must be able to invade distal sites, initiate tumor growth, proliferate, and promote a tumor microenvironment (TME) to evade immune surveillance and promote angiogenesis. Elucidating novel mechanisms that underlie these metastatic phenotypes in DTCs can identify key drivers of metastasis, as well as potential therapeutic vulnerabilities which can better target metastatic tumors. My dissertation research focuses on elucidating the mechanisms in which the lncRNA BORG (BMP/OP-Responsive Gene) drives breast cancer (BC) metastasis. My studies determined that metastatic BC cells are reliant upon BORG complexing with E3 SUMO ligase TRIM28 to induce breast cancer stem cells (BCSCs) to expand and self-renew both in vitro and in vivo. This work establishes BORG as a novel driver of BCSCs, and therefore increases our understanding of the mechanisms driving the accumulation of these malignant cell populations. My recent preliminary data suggests BORG:TRIM28 complexes downregulate the expression of splicing factors in BC cells, which contributes to BCSC phenotypes. Interestingly, accumulating evidence indicates that dysregulation of RNA splicing, a complex molecular tool that can control cellular phenotypes through transcriptomic regulatory mechanisms, contributes to a variety of tumorigenic phenotypes and even metastatic relapse. Therefore, during the F99 portion of this proposal, I seek to elucidate the mechanism whereby BORG:TRIM28 complexes dysregulate RNA splicing operant in driving metastatic and BCSC phenotypes in BC. To complete this research during my dissertation, I will (i) determine which splicing factors dysregulated by BORG:TRIM28 complexes drive metastatic phenotypes in BC in vitro and in vivo, and (ii) use RNAseq and subsequent validation to determine the specific alternative splicing events affected by a subset of these splicing factors in BORG-expressing cells. This work will identify novel mechanisms of RNA splicing regulation that play key roles in metastatic phenotypes of BC cells. During the K00 phase of this proposal, I plan to work closely with my postdoctoral mentor to elucidate the mechanisms in which RNA splicing contributes to tumor cell crosstalk with the TME to promote immune evasion and subsequent metastatic outgrowth. Specifically, I plan to elucidate (i) how alternative splicing in tumor cells drive changes in the metastatic TME to promote immune evasion, and (ii) how alternative splicing changes in TME cells, such as T cells and fibroblasts, contribute to the metastatic niche and subsequent metastatic outgrowth. The current and future goals of my research are to elucidate mechanisms in which dysregulated RNA splicing contributes to metastatic seeding and outgrowth in aggressive cancers. My predoctoral and postdoctoral research will provide me with expertise in the role of RNA splicing in cancer metastasis, and provide me with essential research and professional skills to launch me into my independent research career at a leading research institute.

项目概要/摘要转移是播散性肿瘤细胞（DTC）扩散到远端组织和器官的过程，是癌症相关死亡的主要原因。为了完成转移级联，DTC 必须能够侵入远端部位，启动肿瘤生长、增殖并促进肿瘤微环境（TME）逃避免疫监视并促进血管生成。阐明这些转移背后的新机制 DTC 中的表型可以识别转移的关键驱动因素，以及潜在的治疗漏洞可以更好地靶向转移肿瘤。我的论文研究重点是阐明其中的机制 lncRNA BORG（BMP/OP 响应基因）驱动乳腺癌 (BC) 转移。我的学业决定了转移性 BC 细胞依赖于 BORG 与 E3 SUMO 连接酶 TRIM28 的复合来诱导乳腺癌癌症干细胞（BCSC）在体外和体内均能扩增和自我更新。这项工作将 BORG 确立为 BCSC 的新驱动因素，因此增加了我们对驱动积累机制的理解这些恶性细胞群。我最近的初步数据表明 BORG:TRIM28 复合物下调 BC 细胞中剪接因子的表达，从而导致 BCSC 表型。有趣的是，越来越多的证据表明 RNA 剪接的失调，这是一种复杂的分子工具，可以控制通过转录组调控机制的细胞表型，有助于多种致瘤表型甚至转移复发。因此，在本提案的 F99 部分中，我试图阐明 BORG:TRIM28 复合物失调 RNA 剪接操作以驱动转移和 BC 中的 BCSC 表型。为了在我的论文期间完成这项研究，我将（i）确定哪种剪接 BORG:TRIM28 复合物失调的因素在体外和体内驱动 BC 的转移表型，以及 (ii) 使用 RNAseq 和随后的验证来确定受 a 影响的特定选择性剪接事件 BORG 表达细胞中这些剪接因子的子集。这项工作将确定 RNA 的新机制剪接调节在 BC 细胞的转移表型中发挥关键作用。在该提案的 K00 阶段，我计划与我的博士后导师密切合作，阐明 RNA 剪接的作用机制肿瘤细胞与 TME 相互作用，促进免疫逃避和随后的转移生长。具体来说，我计划阐明 (i) 肿瘤细胞中的选择性剪接如何驱动转移性 TME 的变化促进免疫逃避，以及 (ii) TME 细胞（如 T 细胞和成纤维细胞）中的选择性剪接如何变化，有助于转移生态位和随后的转移生长。我现在和未来的目标研究的目的是阐明RNA剪接失调导致转移性播种和转移的机制。侵袭性癌症的生长。我的博士前和博士后研究将为我提供以下方面的专业知识 RNA剪接在癌症转移中的作用，并为我提供必要的研究和专业技能让我在一家领先的研究机构开始我的独立研究生涯。