Intersectional genetics-based biosensors for dormant cancer cells

基于交叉遗传学的休眠癌细胞生物传感器

• 批准号: 10612300
• 负责人: Jose Javier Bravo-Cordero
• 金额: $ 21.78万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612300
• 关键词: Ablation; Aftercare; Algorithms; Atlases; Biology; Biosensor; Bypass; Cancer Etiology; Cancer Relapse; Cell surface; Cells; Cessation of life; Code; Computational Biology; Custom; Cytotoxin; DNA delivery; Development; Disease; Distant; Enhancers; Frustration; Gene Expression Profile; Generations; Genetic; Genetic Engineering; Genetic Transcription; Genome; Genomics; Goals; Grant; Imaging technology; Malignant Neoplasms; Methods; Modeling; Molecular; Molecular Profiling; Names; Neoplasm Metastasis; Normal Cell; Organ; Output; Patients; Process; Property; Proteins; Psyche structure; Regulator Genes; Regulatory Element; Research; Research Design; Resolution; Source; Specificity; Synthetic Genes; System; Technology; Testing; Translating; cancer cell; cancer type; cell type; cost; cytotoxic; design; diagnostic value; genetic manipulation; genetic technology; high resolution imaging; in vivo; insight; intravital imaging; mouse model; neoplastic cell; new therapeutic target; next generation sequencing; novel therapeutic intervention; novel therapeutics; practical application; prevent; programs; sensor; side effect; success; synergism; synthetic biology; targeted delivery; targeted treatment; tool; tumor; two photon microscopy

PROJECT SUMMARY/ABSTRACT Background: Metastasis in distant organs years after treatment is the primary cause of cancer death. Late progression occurs through the reactivation of dormant tumor cells that disseminated early in the disease. To date, no therapy has been designed to target those cells and the lack of understanding on their biology prevents the development of selective strategies to kill them. We aim to gain molecular insight into the gene regulatory signature of the cancer dormancy state and use this information to devise a dormant cancer cell biosensor that will allow us to identify, profile, and genetically manipulate them in vivo. Hypothesis: We hypothesize that the application of intersectional genetics tools to define the unique transcriptional profile of dormant cells will reveal vulnerabilities that could be exploited to eliminate those cells. Specific Aims: Aim 1. To obtain and validate the enhancer activity profiles of dormant cancer cells in an in vivo context Aim 2. To develop a dormant cancer cell biosensor and test its in vivo potential to selectively identify dormant cancer cells. Study design/Methods: To increase the specificity of dormant cancer cell identification in vivo, reduce side- effects on non-target normal cells, and allow the systematization of the generation of dormant cell-specific biosensors and its downstream applications, such as targeted cell ablation therapies, we propose to develop a new dormant cell biosensor that bypasses cell-surface marker requirements distinguishing them instead via intracellular properties that can be harnessed to allow the precise and exclusive genetic manipulation of these cells within the body. We will validate our biosensor in vivo by using cellular dormancy models and intravital two- photon microscopy. Relevance: The mechanisms of cancer cell dormancy are poorly understood, hence the options available for their targeted treatment to prevent metastasis are limited. Here, we propose to use state-of-the-art genomic activity profiling technology to gain molecular insight into the genetic program that defines the cancer dormancy state in vivo. We will then couple our unique computational and synthetic biology know-how to define unique signatures of the dormancy program to engineer genetic sensors that can be systemically-delivered into the body to find dormant cancer cells. With this strategy, we hope to develop strategies to eliminate metastatic dormant cells, the source of metastasis.

项目摘要/摘要 背景：治疗后几年的遥远器官转移是癌症死亡的主要原因。晚的 进展是通过在疾病早期传播的休眠肿瘤细胞的重新激活而发生的。到 日期，尚未设计任何疗法来靶向这些细胞，并且对生物学缺乏了解可以阻止 杀死他们的选择性策略的发展。我们旨在获得对基因调节的分子见解 癌症休眠状态的签名，并使用此信息来设计一种休眠的癌细胞生物传感器 将使我们能够在体内识别，概况和遗传操纵它们。 假设：我们假设使用交叉遗传学工具来定义独特的遗传学工具 休眠细胞的转录谱将揭示可以利用以消除这些细胞的漏洞。 具体目的：目标1。获得和验证体内休眠癌细胞的增强剂活性谱 上下文目的2。开发休眠的癌细胞生物传感器并测试其体内潜力以选择性地识别 休眠的癌细胞。 研究设计/方法：为了增加体内休眠癌细胞鉴定的特异性，请减少侧面 对非目标正常细胞的影响，并允许系统化休眠细胞特异性的产生 生物传感器及其下游应用，例如靶向细胞消融疗法，我们建议开发一个 新的休眠细胞生物传感器绕过细胞表面标记的要求，通过 可以利用的细胞内特性，以允许对这些的精确和独家的遗传操纵 体内的细胞。我们将通过使用细胞休眠模型和插入性的两种体内验证生物传感器 光子显微镜。 相关性：癌细胞休眠的机制知之甚少，因此可供选择 他们预防转移的目标治疗受到限制。在这里，我们建议使用最先进的基因组 活性分析技术以获得对定义癌症休眠的遗传程序的分子见解 体内状态。然后，我们将对独特的计算和合成生物学专业知识来定义独特 休眠计划的签名与可以系统地交付到体内的遗传传感器的签名 找到休眠的癌细胞。通过这种策略，我们希望制定消除转移性休眠的策略 细胞，转移的来源。