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.

项目概要/摘要 背景：治疗后数年远处器官转移是癌症死亡的主要原因。晚的 进展是通过疾病早期传播的休眠肿瘤细胞的重新激活而发生的。到 迄今为止，还没有针对这些细胞设计治疗方法，并且缺乏对其生物学的了解，阻碍了对这些细胞的研究。 制定选择性策略来杀死它们。我们的目标是从分子角度深入了解基因调控 癌症休眠状态的特征，并利用该信息设计一种休眠癌细胞生物传感器 将使我们能够在体内识别、分析和基因操纵它们。 假设：我们假设应用交叉遗传学工具来定义独特的 休眠细胞的转录谱将揭示可用于消除这些细胞的漏洞。 具体目标： 目标 1. 获得并验证体内休眠癌细胞的增强子活性谱 目标 2. 开发休眠癌细胞生物传感器并测试其体内选择性识别潜力 休眠的癌细胞。 研究设计/方法：提高体内休眠癌细胞识别的特异性，减少副作用 对非靶正常细胞的影响，并允许休眠细胞特异性生成的系统化 生物传感器及其下游应用，例如靶向细胞消融疗法，我们建议开发一种 新的休眠细胞生物传感器绕过细胞表面标记要求，而是通过 细胞内特性可用于对这些特性进行精确且独特的遗传操作 体内的细胞。我们将通过使用细胞休眠模型和活体内两种方法在体内验证我们的生物传感器 光子显微镜。 相关性：对癌细胞休眠的机制知之甚少，因此可用的选择 他们预防转移的针对性治疗是有限的。在这里，我们建议使用最先进的基因组 活动分析技术可从分子角度深入了解定义癌症休眠的遗传程序 体内状态。然后，我们将结合我们独特的计算和合成生物学知识来定义独特的 休眠程序的签名，用于设计可以系统地输送到体内的基因传感器 寻找休眠的癌细胞。通过这一策略，我们希望制定消除转移休眠的策略 细胞，转移的源头。