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.

项目概要 转移是晚期癌症的一个决定性特征，通常代表从可治愈到不可治愈的转变 它主要是由随机过程驱动的，并且预测它何时发生仍然具有挑战性。 对循环肿瘤转移潜力增加的机制进行研究 细胞（CTC）簇通过系统生物学、斑马鱼体内实验和理论相结合 黑色素瘤是最致命的皮肤癌，两者之间表现出特别明显的差异。 已从患有局部疾病和转移性疾病的患者的血液中分离出 CTC 簇的结果。 患有黑色素瘤和其他癌症类型的患者，预示着 CTC 集群的临床预后不佳。 在转移中很重要，但尽管它们很重要，但其形成背后有许多关键机制， 转移能力的增加和治疗靶向的潜力在很大程度上仍未被探索，特别是在 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。 能够移植到透明 Casper 斑马鱼中的黑色素瘤细胞系，为 为此，我们研究了驱动 CTC 簇转移潜力增加的细胞过程。 在奖学金中，我们将讨论 CTC 簇的两个属性以及它们与转移适应性的关系（目标 1）。 我们认为，群体规模和数量之间的权衡（对于生态扩散而言是不可或缺的）是实现这一目标的关键。 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中，表征转移适应性 然后我们将介绍专门针对黑色素瘤 CTC 簇的遗传扰动。 集群协作的线程机制，以阐明 CTC 集群的底层机制 （目标 2）我们努力克服集群内的高多样性促进整体转移适应性。 存在一些个体适应性较低的细胞，我们将通过工程集群来检验这一假设。 我们将应用定量统计分析来比较黑色素瘤特定形式的遗传异质性。 将高多样性和低多样性簇移植到斑马鱼中，评估组成异质性的作用 这两种方法与哺乳动物模型中的验证相结合，将在 CTC 簇转移适应性中发挥重要作用。 对 CTC 簇适应性的大小和组成权衡产生新的见解，可以提供信息 开发黑色素瘤及更广泛领域的新诊断、预后和治疗策略。

项目成果

Regenerative lineages and immune-mediated pruning in lung cancer metastasis.

肺癌转移中的再生谱系和免疫介导的修剪。

• 发表时间: 2020
• 影响因子: 82.9
• 作者: Laughney, Ashley M;Hu, Jing;Campbell, Nathaniel R;Bakhoum, Samuel F;Setty, Manu;Lavallée, Vincent;Xie, Yubin;Masilionis, Ignas;Carr, Ambrose J;Kottapalli, Sanjay;Allaj, Viola;Mattar, Marissa;Rekhtman, Natasha;Xavier, Joao B;Mazutis
• 通讯作者: Mazutis

Regulation of the error-prone DNA polymerase Polκ by oncogenic signaling and its contribution to drug resistance.

通过致癌信号调节容易出错的 DNA 聚合酶 Polγ 及其对耐药性的贡献。

• 发表时间: 2020
• 影响因子: 7.3
• 作者: Temprine, Kelsey;Campbell, Nathaniel R;Huang, Richard;Langdon, Erin M;Simon;Mehta, Krisha;Clapp, Averill;Chipman, Mollie;White, Richard M
• 通讯作者: White, Richard M