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：治疗数年后远处器官转移是癌症死亡的主要原因。晚些 进展是通过在疾病早期扩散的休眠肿瘤细胞重新激活而发生的。至 到目前为止，还没有针对这些细胞的治疗方法，而且对它们的生物学了解的缺乏阻止了 制定选择性的策略来杀死它们。我们的目标是获得对基因调控的分子洞察力 癌症休眠状态的特征，并使用该信息设计一种休眠癌细胞生物传感器 将使我们能够在活体内识别、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 休眠细胞的转录图谱将揭示可以被利用来消除这些细胞的脆弱性。 具体目的：目的：1.获得并验证体内潜伏癌细胞的增强子活性 背景目的2.开发一种休眠癌细胞生物传感器，并测试其在体内选择性识别 休眠的癌细胞。 研究设计/方法：提高体内潜伏癌细胞鉴定的特异性，减少副作用 对非靶标正常细胞的影响，并允许系统化产生休眠细胞特有的 生物传感器及其下游应用，如靶向细胞消融疗法，我们建议开发一种 新型休眠细胞生物传感器，绕过细胞表面标记要求，通过 可以利用细胞内特性来实现对这些基因的精确和排他性的操作 体内的细胞。我们将使用细胞休眠模型和活体内的两个模型在体内验证我们的生物传感器。 光子显微镜。 相关性：癌细胞休眠的机制知之甚少，因此可供选择的治疗方法 他们用来预防转移的靶向治疗是有限的。在这里，我们建议使用最先进的基因组 活动图谱技术，以获得对定义癌症休眠的遗传程序的分子洞察 活体状态。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，以设计可以系统地输送到体内的遗传传感器 去寻找潜伏的癌细胞。通过这种策略，我们希望开发出消除转移休眠状态的策略 细胞，转移的来源。