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: 10228322
• 负责人: Nathaniel R Campbell
• 金额: $ 3.33万
• 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/10228322
• 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; 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; outcome forecast; 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.

项目摘要 转移是晚期癌症的一个定义性特征，通常代表着从可治愈到不可治愈的转变 疾病它在很大程度上是由随机过程驱动的，并且仍然难以预测何时发生。我们 对推动循环肿瘤转移潜力增加的机制进行研究 细胞（CTC）集群通过系统生物学，在斑马鱼体内实验，和理论 生态黑色素瘤，最致命的皮肤癌，显示了一个特别明显的区别， 局部与转移性疾病患者的结局。CTC簇已经从以下动物的血液中分离出来： 黑色素瘤患者以及其他癌症类型，并预示着不良的临床预后。CTC集群是 重要的转移，但尽管他们的重要性，许多关键机制，其形成的基础， 增加的转移能力和治疗靶向的潜力在很大程度上仍未探索，特别是在 黑素瘤我们的研究利用了转移性黑色素瘤的斑马鱼模型，包括斑马鱼 黑色素瘤细胞系能够移植到透明的卡斯珀斑马鱼，提供了一个强大的工具， 研究驱动CTC簇转移潜力增加的细胞过程。为此 奖学金，我们将解决CTC集群的两个属性，以及它们如何与转移健身。(Aim第一章 我们假设，群体大小和数量之间的权衡-生态扩散的组成部分-是关键， CTC簇的转移形成。我们将通过应用定量统计分析来检验这一假设 移植到斑马鱼体内的大小不等的黑色素瘤簇， 黑色素瘤CTC集群的景观。然后我们将引入基因扰动， 为了阐明CTC集群的机制，本文提出了集群合作的假设机制 健身(Aim 2）我们假设，尽管存在高的簇内多样性，但高的簇内多样性促进了整体转移适应性。 存在一些个体适应度较低的细胞。我们将通过工程集群来测试这一假设， 黑色素瘤特有的遗传异质性。我们将应用定量统计分析比较 高和低多样性集群移植到斑马鱼，评估组成异质性的作用 在CTC簇转移适应性中。这两种方法，结合哺乳动物模型的验证，将 对CTC集群适应度的大小和组成权衡产生新的见解， 在黑色素瘤和更广泛的新的诊断，预后和治疗策略的发展。