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.

项目总结/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 疾病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的治疗方法，对它们的生物学缺乏了解， 有选择性地杀死他们我们的目标是获得对基因调控的分子见解， 并使用该信息来设计休眠癌细胞生物传感器，该生物传感器 将使我们能够在体内识别、分析和遗传操纵它们。 假设：我们假设交叉遗传学工具的应用，以确定独特的 休眠细胞的转录谱将揭示可被利用来消除这些细胞的弱点。 具体目标：目标1。为了获得并验证体内休眠癌细胞的增强子活性谱， 目标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：为了提高体内休眠癌细胞识别的特异性，减少副作用， 对非靶正常细胞的作用，并允许系统化的休眠细胞特异性的产生， 生物传感器及其下游应用，如靶向细胞消融治疗，我们建议开发一种 新的休眠细胞生物传感器，绕过细胞表面标志物的要求，而不是通过 细胞内的特性，可以利用，以允许精确和排他性的遗传操纵这些 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来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， 其防止转移的靶向治疗有限。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洞察 体内状态。然后，我们将结合我们独特的计算和合成生物学专业知识来定义独特的 休眠程序的签名，以设计可以系统地传递到体内的遗传传感器， 寻找休眠的癌细胞有了这个策略，我们希望制定策略，以消除转移性休眠 细胞，转移的来源。