The pluripotency regulator Prdm14 initiates cancer by epigenetic mechanisms

多能性调节因子 Prdm14 通过表观遗传机制引发癌症

基本信息

批准号：
8844112
负责人：
MONICA J. JUSTICE
金额：
$ 31.99万
依托单位：
HOSPITAL FOR SICK CHLDRN (TORONTO)
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-28 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8844112
关键词：
Address Adult Aftercare Aneuploidy Animals Behavior Binding Biochemical Biological Assay Breast Cancer Relapse Cell Separation Cells Chromatin Chromosomal Rearrangement Colon Complex Copy Number Polymorphism Cultured Cells DNA DNA Damage DNA Repair DNA Repair Pathway Derivation procedure Development Disease Double Strand Break Repair Drug resistance Epigenetic Process Event Flow Cytometry Functional RNA Gene Expression Profile Gene Targeting Genes Genetic Genetic Recombination Genome Genomic Instability Genomics Goals Health Human Life Link Lymphoblastic Leukemia Maintenance Malignant Neoplasms Mediating Messenger RNA MicroRNAs Mining Modeling Molecular Molecular Profiling Monitor Mus Mutation NOTCH1 gene Ovarian Pharmaceutical Preparations Play Property Proteins RNA Sequences Radiation Recurrent disease Relapse Reporter Resistance Role SET Domain Signal Transduction Somatic Cell Stem cells Structure of primordial sex cell Therapeutic Therapeutic Intervention Tissues Work X Chromosome Xenograft Model anticancer research base cancer cell cancer initiation cancer prevention cancer type cell type chemotherapeutic agent chromatin remodeling clinically relevant combinatorial demethylation design histone methyltransferase human data interest leukemia lung melanoma molecular marker mouse model pluripotency preclinical study prevent programs protein complex research study response self-renewal stem transcription factor treatment strategy tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Drug resistance and cancer relapse are attributed to the persistence of stem cells. The PR/SET domain protein PRDM14 regulates a cell's pluripotent potential to initiate and progress cancer through epigenetic events that are molecular signatures of stem cells. Normally, PRDM14 uses epigenetic mechanisms to establish the pluripotency of primordial germ cells, and its role in cancer is similar. PRDM14's widespread expression in many tumor types, including breast, ovarian, colon, lung, melanoma and lymphoblastic leukemia implies that it is commonly involved in epigenetic events to initiate cancer. This proposal challenges paradigms by suggesting that PRDM14 regulates a somatic cell's pluripotent potential to generate C-ICs as it promotes genomic instability, allowing it to cause tumors in many cell types. PRDM14 is a prime target for therapeutic intervention, because of its restricted expression to only a few cells in the body. Key to this project is that unique inducible mouse models will be exploited to examine events during tumor development, progression and relapse. Experiments that address three basic questions will be performed: what biochemical mechanisms does Prdm14 use to establish self-renewal to initiate cancer, how do the initiating cells maintain self-renewal in the tumor, and how does PRDM14 perturb genome integrity within these cells to progress malignancy? The first aim will use cutting edge genomic approaches to confirm Prdm14's binding targets and identify its protein partners, while it determines how Prdm14 alters chromatin to reset pluripotency in pre- leukemia cells. The second aim will determine the properties of Prdm14 pre-leukemia cells using flow cytometry, cellular and molecular profiling approaches. The third aim will determine how PRDM14 catalyzes chromosomal rearrangements, leading to copy number variation in the tumors that cause specific driver mutations such as activated NOTCH1 through recombination. These studies propose a genetic strategy to inhibit recombination and a drug treatment strategy designed against targets downstream of PRDM14's action to prevent the growth of tumors in the mouse model. The mouse models allow the behavior of cancer cells to be monitored from the beginning, mark cells for isolation, and follow their lineage potential. Data from human tumors will be mined and compared with mouse tumors throughout the study and mouse leukemia will be compared with human leukemia in Aim 3 to demonstrate clinical relevance. Although mouse leukemia models are exploited, the work will have far-reaching applications to all cancers. PRDM14's limited normal expression in adults indicates that PRDM14 or its initial regulatory targets are key candidates for a therapy directed against cells that express it abnormally. Therefore, PRDM14 could prove to be a universal target in C-ICs.

描述（由申请人提供）：耐药性和癌症复发归因于干细胞的持久存在。 PR/SET 结构域蛋白 PRDM14 通过表观遗传事件（干细胞的分子特征）调节细胞的多能潜能，从而引发和进展癌症。通常，PRDM14利用表观遗传机制来建立原始生殖细胞的多能性，其在癌症中的作用类似。 PRDM14在许多肿瘤类型中广泛表达，包括乳腺癌、卵巢癌、结肠癌、肺癌、黑色素瘤和淋巴细胞白血病，这意味着它通常参与引发癌症的表观遗传事件。该提案挑战了范式，表明 PRDM14 调节体细胞产生 C-IC 的多能潜力，因为它促进基因组不稳定性，从而在许多细胞类型中引起肿瘤。 PRDM14 是治疗干预的主要靶标，因为它的表达仅限于体内少数细胞。该项目的关键是利用独特的诱导小鼠模型来检查肿瘤发展、进展和复发过程中的事件。将进行解决三个基本问题的实验：Prdm14 使用什么生化机制来建立自我更新以引发癌症，起始细胞如何在肿瘤中维持自我更新，以及 PRDM14 如何扰乱这些细胞内的基因组完整性以促进进展恶性肿瘤？第一个目标将使用尖端的基因组方法来确认 Prdm14 的结合靶标并识别其蛋白质伴侣，同时确定 Prdm14 如何改变染色质以重置白血病前期细胞的多能性。第二个目标将使用流式细胞术、细胞和分子分析方法确定 Prdm14 白血病前期细胞的特性。第三个目标将确定 PRDM14 如何催化染色体重排，从而导致肿瘤中的拷贝数变异，从而导致特定的驱动突变，例如通过重组激活 NOTCH1。这些研究提出了一种抑制重组的遗传策略，以及一种针对 PRDM14 下游靶点设计的药物治疗策略，以防止小鼠模型中肿瘤的生长。小鼠模型可以从一开始就监测癌细胞的行为，标记细胞进行分离，并追踪它们的谱系潜力。在整个研究过程中，将挖掘人类肿瘤的数据并与小鼠肿瘤进行比较，并且在目标 3 中将小鼠白血病与人类白血病进行比较，以证明临床相关性。尽管利用了小鼠白血病模型，但这项工作将对所有癌症产生深远的应用。 PRDM14 在成人中有限的正常表达表明 PRDM14 或其初始调节靶点是针对异常表达的细胞的治疗的关键候选者。因此，PRDM14 可能被证明是 C-IC 中的通用靶标。