(PQB6)Elucidating metastasis by real-time monitoring and tagging of CTCs in GEMMs

(PQB6)通过实时监测和标记 GEMM 中的 CTC 来阐明转移

• 批准号: 8836990
• 负责人: TYLER E. JACKS
• 金额: $ 61.11万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8836990
• 关键词: Address; Angiogenesis Inhibitors; Back; Biopsy; Blood; Blood Circulation; Blood Volume; Cardiovascular system; Catheters; Cell Count; Cells; Characteristics; Climacteric; Collection; Computer Systems; Diagnosis; Disease; Distant; Distant Metastasis; Gene Expression Profiling; Genetically Engineered Mouse; Half-Life; Health; Heterogeneity; Label; Life; Link; Liquid substance; Longitudinal Studies; Measurement; Measures; Mechanics; Methods; Microfluidics; Monitor; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Organ; Patients; Physiologic arteriovenous anastomosis; Population; Population Heterogeneity; Primary Neoplasm; Reporter; Role; Sampling; Seeds; Series; Shunt Device; Staging; System; Techniques; Technology; Therapeutic; Time; Tumor Biology; Tumor Burden; Venous; base; cancer cell; cancer therapy; chemotherapy; human disease; insight; mouse model; neoplastic cell; novel; operation; pre-clinical; research study; response; time use; tumor; tumor initiation; tumor progression

DESCRIPTION (provided by applicant): Despite the central importance of circulating tumor cells (CTCs), understanding of their role in metastasis has been limited by the extreme difficulty of characterizing CTC populations over time and linking them to metastases that occur during natural tumor progression. We propose to develop a novel system that enables longitudinal and dynamic CTC studies in genetically engineered mouse models (GEMMs). The system will make possible a series of experiments that can answer fundamental questions about the relationship between CTC characteristics and metastasis: Does the time that CTCs remain in the circulatory system (half-life) change during tumor progression? Are cancer cells in primary tumors predisposed to form metastases soon after initiation or must tumors evolve to acquire metastatic potential? Do chemotherapeutic or anti-angiogenic agents promote CTC intravasation and increase the likelihood of distant metastasis? Beyond the scope of these fundamental questions, developing a system that enables liquid biopsies for dynamic and longitudinal CTC studies in GEMMs will potentiate hypothesis-driven tumor biology studies and large-scale preclinical exploration of therapeutic strategies that are not feasible in patients. Our proposed system will use mice with fluorescent reporters that brightly label all tumor cells, including CTCs a surgically installed arterio-venous shunt; and a microfluidic cell sorter controlled by a real-tie computer system. In operation, the majority of blood from a live mouse will pass through the system and return via catheter. Each time a fluorescent CTC passes through the sorter, the control system will divert a small volume of blood including the CTC to a collection port, producing a dramatically enriched CTC sample. The sample can be further concentrated and manipulated by a variety of techniques.

描述（由申请人提供）：尽管循环肿瘤细胞（CTC）的重要性，但对它们在转移中的作用的理解受到了表征CTC种群随时间并将其与自然肿瘤进展过程中发生的转移酶联系起来的极端困难。我们建议开发一种新型系统，该系统可以在基因工程小鼠模型（GEMM）中纵向和动态CTC研究。该系统将使一系列实验可以回答有关CTC特征与转移之间关系的基本问题的一系列实验：CTC在肿瘤进展过程中是否保留在循环系统（半衰期）中的时间？原发性肿瘤中的癌细胞是否在开始后不久就会形成转移，还是必须演变为获得转移性潜力？化学治疗或抗血管生成剂是否会促进CTC侵入并增加远处转移的可能性？除了这些基本问题的范围之外，开发了一个系统，该系统能够在宝石中进行动态和纵向CTC研究的液体活检，这将增强假设驱动的肿瘤生物学研究以及对患者不可行的治疗策略的大规模临床前探索。我们提出的系统将使用小鼠与荧光记者使用，这些记者将所有肿瘤细胞（包括CTC a手术安装的动脉连接分流）贴上明智的标记；以及由真实计算机系统控制的微流体细胞分系程序。在运行中，来自活小鼠的大多数血液将通过系统并通过导管返回。每次荧光CTC通过混乱器时，控制系统都会将包括CTC在内的少量血液转移到集合端口，从而产生巨大富集的CTC样品。可以通过多种技术进一步浓缩样品并操纵样品。