(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: 9330805
• 负责人: TYLER E. JACKS
• 金额: $ 59.4万
• 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 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330805
• 关键词: Address; Alpha Cell; Angiogenesis Inhibitors; Back; 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; Heterogeneity; Label; Link; Longitudinal Studies; Measurement; Measures; Mechanics; Methods; Microfluidics; Monitor; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Operative Surgical Procedures; Organ; Patients; Physiologic arteriovenous anastomosis; Population; Population Heterogeneity; Primary Neoplasm; Reporter; Role; Sampling; Seeds; Series; System; Techniques; Technology; Therapeutic; Time; Tumor Biology; Tumor Burden; Tumor stage; base; cancer cell; cancer therapy; chemotherapy; experimental study; human disease; insight; liquid biopsy; mouse model; neoplastic cell; novel; operation; pre-clinical; public health relevance; 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）具有核心重要性，但对它们在转移中的作用的理解受到限制，因为随着时间的推移，CTC群体的特征非常困难，并且将它们与自然肿瘤进展期间发生的转移联系起来。我们建议开发一种新的系统，使纵向和动态CTC研究在基因工程小鼠模型（GEMM）。该系统将使一系列实验成为可能，这些实验可以回答有关CTC特征与转移之间关系的基本问题：CTC在循环系统中保留的时间（半衰期）在肿瘤进展过程中是否会发生变化？原发性肿瘤中的癌细胞是否易于在开始后不久形成转移，或者肿瘤必须进化以获得转移潜能？化疗药物或抗血管生成药物是否促进CTC内渗并增加远处转移的可能性？在这些基本问题的范围之外，开发一种能够在GEMM中进行动态和纵向CTC研究的液体活检系统将加强假设驱动的肿瘤生物学研究和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带有荧光报告分子的小鼠，这些荧光报告分子明亮地标记所有肿瘤细胞，包括CTCs，手术安装的动静脉分流器;以及由实时计算机系统控制的微流体细胞分选仪。在操作中，来自活小鼠的大部分血液将通过系统并经由导管返回。每次荧光CTC通过分选机时，控制系统将把包括CTC的少量血液转移到收集口，产生显著富集的CTC样品。样品可以通过各种技术进一步浓缩和操作。