Amyloid-bodies and the Evolution of Malignancies

淀粉样蛋白体和恶性肿瘤的进化

• 批准号: 10736039
• 负责人: Stephen Lee
• 金额: $ 38.82万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-07 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736039
• 关键词: Acidosis; Amyloid; Animal Model; Applications Grants; Balbiani Body; Biochemical; Biological; Biological Assay; Catalytic Domain; Cell Cycle Regulation; Cells; Clinical; DNA biosynthesis; DNA-Directed DNA Polymerase; Data; Dedications; Depressed mood; Detection; Dinucleotide Repeats; Elements; Environment; Enzyme Activation; Enzymes; Evolution; Genetic Transcription; Germ Cells; Growth; Human; Human Genome; Hypoxia; Immobilization; Junk DNA; Liquid substance; Malignant - descriptor; Malignant Neoplasms; Mediating; Membrane; Metabolic; Metabolism; Names; Nature; Normal tissue morphology; Nuclear Envelope; Nucleic Acids; Oncogenic; Organelles; Participant; Pathway interactions; Phase Transition; Phenotype; Physical condensation; Physiological; Play; Process; Proliferating; Protein Array; Proteins; Proteome; Proteomics; Publishing; RNA; Reporting; Reproduction spores; Ribosomal RNA; Ribosomes; Role; Sampling; Signal Transduction; Solid; Stimulus; Stress; System; Tail; Testing; Untranslated RNA; Xenopus; Yeasts; amyloid formation; amyloidogenesis; biophysical properties; cancer cell; cell assembly; extracellular; fascinate; granule cell; in vivo; malignant phenotype; metabolic depression; neoplastic cell; programs; response; solid state; stress granule; stressor; tumor; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

Amyloid-bodies and the Evolution of Malignancies Project Summary The ability of cancer cells to adapt to a wide variety of stress conditions plays a critical role in various physiological facets of tumorigenesis. We recently reported the discovery of stress-induced low complexity noncoding RNA derived from stimuli-specific loci of the ribosomal intergenic spacer (rIGSRNA); an enigmatic region of the human genome historically dismissed as “junk” DNA. We showed that low complexity rIGSRNA activate a physiological amyloidogenic program that converts nucleoli into Amyloid-bodies: reversible nuclear membrane-less compartments composed of immobilized proteins in an amyloid-like state. While many cellular bodies have been described as liquid-like (e.g., stress granules, P-bodies, germ cell granules), the discovery of Amyloid-bodies provided evidence of an amyloidogenic program that can physiologically transition biological matter to a solid state. Amyloid-bodies are found in sub-populations of cells in normal tissues, the core of low- grade human tumors and cells responding to various stimuli highlighting their ubiquitous nature. Proteomic analysis revealed that Amyloid-bodies immobilize participants of the DNA synthesis machinery and cell cycle control, amongst many other metabolic regulators. Intriguingly, Amyloid-bodies share many biophysical properties with the amyloidogenic, solid-like Balbiani-bodies involved in metabolic suppression in Xenopus. Likewise, yeast solidify elements of their proteome to sporulate and arrest growth in non-permissive conditions. This raises the fascinating possibility that stressed cancer cells assemble Amyloid-bodies to enter a spore-like state of extreme metabolic depression. In this grant proposal, we will show preliminary data that low complexity rIGSRNA coordinate unusual RNA tailing programs to drive system-wide amyloidogenic phase transition. This post-translational pathway enables cancer cells to immobilize elements of the DNA synthesis machinery and halt oncogenic signaling in an adaptive response to severe environmental insults. Based on these preliminary and published results, we hypothesize that “Nucleolar phase transition programs temporarily suspend oncogenicity”. We plan to test this hypothesis by: 1- Uncovering mechanisms of physiological phase transition; 2- Examining how low complexity rIGSRNA activate RNA tailing programs; 3- Demonstrating a role for RNA tailing-mediated phase transition in tumorigenesis. The discovery of dedicated enzymatic programs that drive physiological amyloidogenesis provides a unique opportunity to study the role of liquid-to-solid phase transition in human clinical samples and in vivo tumor assays. By studying clinical samples, in culture and orthotopic animal models, we will test if phase transition induces a unique and yet uncharacterized cancer cell state of extreme metabolic depression, while highlighting biochemical functions for low complexity RNA typically discarded as useless nucleic acids.

淀粉样体和恶性肿瘤的演变 项目摘要 癌细胞适应多种应力条件的能力在各种中起着至关重要的作用 肿瘤发生的生理方面。我们最近报道了压力引起的低复杂性的发现 源自核糖体间间隔物（RIGSRNA）的刺激特异性位置的非编码RNA；一个神秘的 历史上，人类基因组地区被视为“垃圾” DNA。我们证明了低复杂性rigsrna 激活将核仁转化为淀粉样物体的物理淀粉样生成程序：可逆核 由淀粉样蛋白状态下的固定蛋白组成的无膜隔室。而许多细胞 身体已被描述为液体样（例如，应力颗粒，p-bodies，生殖细胞颗粒），发现 淀粉样体提供了淀粉样蛋白生成程序的证据，可以物理过渡生物学 至关重要。在正常时间的细胞亚群中发现了淀粉样体，低 - 的核心 对各种刺激的反应型人类肿瘤和细胞级，突出了它们的无处不在的性质。蛋白质组学 分析表明，淀粉样体可以固定DNA合成机制和细胞周期的参与者 控制，在许多其他代谢调节剂中。有趣的是，淀粉样体共享许多生物物理 具有淀粉样蛋白生成的，固体样巴尔比亚体的特性，参与异武氏代谢抑制。 同样，酵母固化其蛋白质组的元素，以在非抗药性条件下孢子生长。 这增加了一种令人着迷的可能性，即压力癌细胞组装淀粉样体以进入散射状的可能性 极端代谢抑郁症的状态。在此赠款提案中，我们将显示初步数据的复杂性 RIGSRNA协调了异常的RNA尾部程序，以驱动整个系统淀粉样蛋白生成相变。这 翻译后途径使癌细胞能够固定DNA合成机制的元素并停止 对严重环境侮辱的自适应反应中的致癌信号传导。基于这些初步 发表的结果，我们假设“核仁相变计划暂时暂停致癌性”。 我们计划通过：1-揭示物理相变的机制来检验这一假设； 2-检查 复杂性rigsRNA如何激活RNA尾部程序； 3-演示RNA尾介介导的作用 肿瘤发生中的相变。发现专门的酶促程序，这些程序驱动生理 淀粉样生成提供了一个独特的机会，可以研究人类液相变的作用 临床样品和体内肿瘤分析。通过研究临床样本，培养和原位动物模型中的 我们将测试相位过渡是否诱导极端代谢的独特但未表征的癌细胞状态 抑郁症，同时突出显示低复杂性的生化功能，通常被丢弃为无用 核酸。