Dissecting the Ecology of Metastasis in a Zebrafish Model: Trade-Offs of Size and Diversity in Circulating Tumor Cell Clusters

剖析斑马鱼模型中转移的生态学：循环肿瘤细胞簇大小和多样性的权衡

• 批准号: 10247091
• 负责人: Nathaniel R Campbell
• 金额: $ 5.1万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247091
• 关键词: Address; Advanced Malignant Neoplasm; Animals; Apoptosis; Automobile Driving; Blood; Blood Circulation; Cell Line; Cell physiology; Cells; Clinical; Cooperative Behavior; Cyclic AMP; Development; Disease; Drug Targeting; Ecology; Engineering; Epigenetic Process; Event; Fellowship; Gene Expression Profiling; Genetic; Genetic Heterogeneity; Growth; Heterogeneity; Human; Image Analysis; Imaging Techniques; Immune; Individual; Intravenous; Investigation; Maintenance; Malignant Neoplasms; Mediator of activation protein; Melanoma Cell; Metastatic Melanoma; Metastatic to; Modeling; Molecular; Neoplasm Circulating Cells; Neoplasm Metastasis; Organism; Pathway Analysis; Patient-Focused Outcomes; Patients; Pharmacology; Probability; Process; Prognosis; Property; Quantitative Microscopy; Role; Signal Transduction; Site; Skin Cancer; Statistical Data Interpretation; Statistical Models; Stochastic Processes; Systems Biology; Techniques; Testing; Therapeutic; Tissues; Transplantation; Tumor Burden; Validation; Work; Zebrafish; base; cancer cell; cancer type; experimental study; fitness; genetic manipulation; human model; in vivo; insight; intravital imaging; intravital microscopy; mathematical model; melanoma; novel diagnostics; prevent; prognostic; quantitative imaging; success; therapeutic target; tool; tumor progression

PROJECT SUMMARY Metastasis is a defining feature of advanced cancer, often representing a transition from curable to incurable disease. It is largely driven by stochastic processes, and remains challenging to predict when it will occur. We undertake an investigation into the mechanisms driving the increased metastatic potential of circulating tumor cell (CTC) clusters through a combination of systems biology, in vivo experiments in zebrafish, and theoretical ecology. Melanoma, the most lethal of skin cancers, shows a particularly stark difference between the outcomes of patients with local versus metastatic disease. CTC clusters have been isolated from the blood of patients with melanoma, among other cancer types, and portend a poor clinical prognosis. CTC clusters are important in metastases, but despite their importance many key mechanisms underlying their formation, increased metastatic capacity, and potential for therapeutic targeting remain largely unexplored, particularly in melanoma. Our study takes advantage of the zebrafish model of metastatic melanoma, including zebrafish melanoma cell lines capable of transplantation into transparent Casper zebrafish, providing a powerful tool for investigating the cellular processes driving the increased metastatic potential of CTC clusters. For this fellowship, we will address two properties of CTC clusters and how they relate to metastatic fitness. (Aim 1) We hypothesize that the trade-off between group size and number—integral to ecological dispersal—is key in metastasis formation by CTC clusters. We will test this hypothesis by applying quantitative statistical analysis to melanoma clusters of varying size transplanted into zebrafish, characterizing the metastatic fitness landscape of melanoma CTC clusters. We will then introduce genetic perturbations specifically targeting hypothesized mechanisms of cluster cooperation in order to elucidate the mechanisms underlying CTC cluster fitness. (Aim 2) We hypothesize that high intra-cluster diversity promotes overall metastatic fitness despite the presence of some cells with lower individual fitness. We will test this hypothesis by engineering clusters with melanoma-specific forms of genetic heterogeneity. We will apply quantitative statistical analysis comparing high- and low-diversity clusters transplanted into zebrafish, evaluating the role of compositional heterogeneity in CTC cluster metastatic fitness. These two approaches, combined with validation in mammalian models, will generate new insights into the size and compositional trade-offs underlying CTC cluster fitness that can inform the development of new diagnostic, prognostic and therapeutic strategies in melanoma and more broadly.

项目总结 转移是晚期癌症的一个决定性特征，通常代表着从可治愈到不可治愈的过渡。 疾病。它在很大程度上是由随机过程驱动的，预测它何时发生仍然具有挑战性。我们 探讨循环肿瘤转移潜能增加的机制 系统生物学、斑马鱼体内实验和理论研究相结合的细胞(CTC)集群 生态学。黑色素瘤是最致命的皮肤癌，它显示出与 局部和转移性疾病患者的转归。从人的血液中分离出CTC簇 在其他癌症类型中，黑色素瘤患者预示着不良的临床预后。CTC集群是 在转移中很重要，但尽管它们很重要，但它们的形成背后有许多关键机制， 增加的转移能力和治疗靶向的潜力在很大程度上仍未被探索，特别是在 黑色素瘤。我们的研究利用了斑马鱼转移性黑色素瘤的模型，包括斑马鱼 能够移植到透明Casper斑马鱼的黑色素瘤细胞系，为 研究推动CTC簇转移潜能增加的细胞过程。为了这个 作为团契，我们将讨论CTC簇的两个特性以及它们与转移适合性的关系。(目标1) 我们假设，种群规模和数量之间的权衡--生态扩散不可或缺的--是 由CTC簇形成的转移。我们将通过应用定量统计分析来检验这一假设 将不同大小的黑色素瘤簇移植到斑马鱼体内，表征转移的适合性 黑色素瘤CTC聚集区景观。然后我们将引入基因扰动，专门针对 假设的集群合作机制，以阐明四氯化碳集群的基础机制 健身。(目标2)我们假设高的集群内多样性促进了整体的转移适应度，尽管 一些个体适合度较低的细胞的存在。我们将通过设计集群来检验这一假设 黑色素瘤特有的遗传异质性形式。我们将采用定量统计分析的方法进行比较 将高多样性和低多样性簇移植到斑马鱼中，评估成分异质性的作用 在CTC簇中转移适合性。这两种方法，结合在哺乳动物模型中的验证，将 对CTC集群适合性背后的规模和组成权衡产生新的见解，从而为 黑色素瘤和更广泛的新诊断、预后和治疗策略的发展。