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.

项目摘要 转移是晚期癌症的定义特征，通常代表从可治愈到无法治愈的过渡 疾病。它在很大程度上是由随机过程驱动的，并且仍然是预测何时发生的挑战。我们 对推动循环肿瘤的转移潜力增加的机制进行调查 细胞（CTC）通过系统生物学的组合，斑马鱼的体内实验和理论的结合 生态。黑色素瘤是最致命的皮肤癌，在 局部与转移性疾病患者的结果。 CTC群集已经从血液中分离出来 黑色素瘤患者除其他癌症类型，并预示着临床预后不佳。 CTC簇是 在转移中很重要，但要努力其重要性的重要性，其形成的许多关键机制， 增加转移能力和热靶向的潜力仍然很出乎意料，尤其是在 黑色素瘤。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将其移植到透明的卡斯珀斑马鱼中，为 研究促进CTC簇的转移潜力增加的细胞过程。为了这 研究金，我们将讨论CTC簇的两个属性及其与转移性适应性的关系。 （目标1） 我们假设群体规模和数量之间的权衡 - 与生态散布的一致性 - 是关键 CTC簇形成转移。我们将通过应用定量统计分析来检验这一假设 到移植到斑马鱼的变化大小的黑色素瘤簇，表征转移性适应性 黑色素瘤CTC簇的景观。然后，我们将引入专门针对的遗传扰动 群集合作的假设机制，以阐明CTC群集的基础机制 健康。 （目标2）我们假设高群内多样性促进了整体转移性健身dospite 某些具有较低个人适应性的细胞的存在。我们将通过与 黑色素瘤特异性的遗传异质性。我们将采用比较定量统计分析 高多样性簇移植到斑马鱼中，评估复合异质性的作用 在CTC簇转移性适应性中。这两种方法与哺乳动物模型中的验证相结合，将 对CTC群集健身的大小和组成权衡产生新的见解，可以告知 在黑色素瘤以及更广泛的诊断，预后和治疗策略的发展。