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.

淀粉样体与肿瘤的进化 项目摘要 癌细胞适应各种应激条件的能力在各种癌症中起着关键作用。 肿瘤发生的生理学方面。我们最近报道了压力诱导的低复杂性的发现 来自核糖体基因间间隔区（rIGSRNA）的刺激特异性位点的非编码RNA;一种神秘的 人类基因组中的一个区域在历史上被认为是“垃圾”DNA。我们发现低复杂度的rIGSRNA 激活将核仁转化为淀粉样体的生理性淀粉样蛋白生成程序： 由淀粉样状态的固定化蛋白质组成的无膜区室。虽然许多细胞 物体被描述为液体状（例如，压力颗粒，P-体，生殖细胞颗粒），发现 淀粉样小体提供了淀粉样蛋白生成程序的证据，该程序可以在生理上将生物学转变为 变成固态。淀粉样体存在于正常组织的细胞亚群中，是低蛋白血症的核心。 分级人类肿瘤和细胞对各种刺激的反应，突出了它们普遍存在的性质。蛋白组 分析表明，淀粉样体参与DNA合成机制和细胞周期 控制，以及许多其他代谢调节剂。有趣的是，淀粉样蛋白体与其他蛋白体 爪蟾中参与代谢抑制的致淀粉样蛋白、固体样巴尔比尼体的特性。 同样，酵母固化其蛋白质组的元素以形成孢子并在非允许条件下抑制生长。 这就提出了一个令人着迷的可能性，即受到压力的癌细胞会组装淀粉样体，进入孢子样结构， 极度代谢性抑郁的状态在这份拨款申请中，我们将展示初步数据， rIGSRNA协调不寻常的RNA加尾程序以驱动系统范围的淀粉样蛋白生成相变。这 翻译后途径使癌细胞能够破坏DNA合成机制的元件， 致癌信号在严重环境损伤的适应性反应。根据这些初步和 根据已发表的结果，我们假设“核仁相变程序暂时中止了致癌性”。 我们计划通过以下几个方面来验证这一假设：1-揭示生理相变的机制; 2-检查 低复杂性rIGSRNA如何激活RNA加尾程序; 3-证明RNA加尾介导 肿瘤发生中的相变。发现专用的酶程序， 淀粉样蛋白的形成为研究人类细胞液-固相转变的作用提供了一个独特的机会。 临床样品和体内肿瘤测定。通过研究临床样本，在培养和原位动物模型中， 我们将测试相变是否会诱导一种独特的、尚未被表征的癌细胞极端代谢状态， 抑郁症，同时强调低复杂性RNA的生化功能，通常被视为无用而丢弃 核酸