Dissecting the complexity of metastasis with mathematical models and quantitative experiments with in zebrafish

用数学模型和斑马鱼定量实验剖析转移的复杂性

• 批准号: 10228581
• 负责人: Richard Mark White
• 金额: $ 63.17万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228581
• 关键词: Address; Advanced Malignant Neoplasm; Affect; Animals; Apoptosis; Automobile Driving; Blood; Blood Circulation; Cancer Etiology; Cell Line; Cells; Cessation of life; Clinical; Collaborations; Computing Methodologies; Conflict (Psychology); Coupled; Cyclic AMP; Data; Development; Differential Equation; Diffuse; Diffusion; Disease; Distant; Ecology; Engineering; Epigenetic Process; Event; Evolution; Genetic; Genetic Heterogeneity; Goals; Heterogeneity; Hydrogen Peroxide; Image; In Vitro; Individual; Laboratories; Lactic acid; Malignant Neoplasms; Mathematics; Melanoma Cell; Metastatic Melanoma; Metastatic to; Methods; Modeling; Molecular; Mutation; Neoplasm Circulating Cells; Neoplasm Metastasis; Organism; Oxygen; Patient-Focused Outcomes; Patients; Peroxides; Probability; Process; Publications; Reaction; Reporter; Resources; Role; Series; Shapes; Signal Transduction; Site; Skin Cancer; Statistical Data Interpretation; System; Testing; Therapeutic; Time; Tissues; Transplantation; Tumor Burden; Validation; Zebrafish; base; cancer cell; cancer therapy; cancer type; experimental study; fitness; improved; in silico; in vivo; in vivo imaging; innovation; insight; intravital imaging; intravital microscopy; lens; mathematical model; melanoma; novel diagnostics; prognostic; social; solute; success; theories; therapeutic target; tool

Project Summary Metastasis—a defining feature of advanced cancer—often represents a transition from curable to incurable disease. The metastatic cascade consists of a series of severe obstacles that cancer cells must overcome, each one highly inefficient and apparently stochastic; we are presently unable to predict whether, when and where metastases will occur. We propose to apply an ecological lens to metastasis. Specifically, we will investigate the processes driving the increased metastatic potential of circulating tumor cell (CTC) clusters through a combination of mathematical modeling and in vivo quantitative experiments in a zebrafish model of melanoma. Melanoma, the most lethal of skin cancers, shows a particularly stark difference between the outcomes of patients with local versus metastatic disease: Patients with CTC clusters in their blood have worse clinical prognoses. Despite their importance, the mechanisms underlying CTC cluster formation, increased metastatic capacity, and potential for therapeutic targeting remain understudied—particularly in melanoma. We take advantage of the zebrafish model of metastatic melanoma, including the ZMEL1 cell line capable of transplantation into transparent Casper zebrafish, which provides a powerful system to quantitatively investigate the mechanisms behind increased metastatic potential of CTC clusters from an ecological perspective. Our three specific aims address how CTC clusters 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 we will test this hypothesis with mathematical models to predict how the success of melanoma clusters varies with size, and we will confront those models with zebrafish data to quantify the metastatic fitness landscape of melanoma CTC clusters; we will then introduce genetic perturbations on hypothesized mechanisms of cellular cooperation within-clusters and elucidate the mechanisms underlying the shape of the cluster fitness landscape. (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 analyses to compare high- and low-diversity clusters transplanted into zebrafish and evaluate the role of compositional heterogeneity in CTC cluster metastatic fitness using multi-level selection theory. (Aim 3) We hypothesize that microenvironmental gradients of diffusible substances determine the success of clusters of extravasated cells; we will test this hypothesis by investigating gradients in vivo, in vitro and in silico using an agent-based model with partial differential equations of reaction-diffusion. These aims, coupled with validation in mammalian models, will generate new insights into the dynamical processes underlying CTC cluster fitness towards the development of new diagnostic, prognostic and therapeutic strategies in melanoma and other cancers.

项目摘要 转移--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转变 疾病转移级联反应由癌细胞必须克服的一系列严重障碍组成， 每一个都是非常低效和明显随机的;我们目前无法预测是否，何时和 会发生转移我们建议应用生态透镜转移。具体来说，我们将 研究驱动循环肿瘤细胞（CTC）簇转移潜力增加的过程 通过在斑马鱼模型中的数学建模和体内定量实验的组合， 黑素瘤黑色素瘤，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：血液中有CTC簇的患者 临床经验尽管其重要性，CTC簇形成的机制，增加 转移能力和治疗靶向的潜力仍然研究不足-特别是在黑素瘤中。我们 利用转移性黑色素瘤的斑马鱼模型，包括能够 移植到透明的卡斯珀斑马鱼，这提供了一个强大的系统，定量 研究CTC簇转移潜能增加背后的机制， perspective.我们的三个具体目标解决CTC簇如何与转移适应性相关：（目标1）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 我们将用数学模型来检验这一假设，以预测 黑色素瘤集群的成功是如何随大小而变化的，我们将用斑马鱼的数据来对抗这些模型。 为了量化黑色素瘤CTC簇的转移适应度，我们将引入遗传学方法， 扰动的假设机制的细胞合作内集群和阐明 集群健身景观的形状背后的机制。(Aim 2）我们假设，高内- 簇多样性促进整体转移适应性，尽管存在一些具有较低个体差异的细胞， 健康;我们将通过用黑色素瘤特异性遗传形式的工程集群来测试这一假设。 异质性;我们将应用定量统计分析来比较高多样性和低多样性集群 移植到斑马鱼中，并评估组成异质性在CTC簇转移中的作用 多层次选择理论。(Aim 3）我们假设，微环境梯度的 可扩散物质决定了外渗细胞簇的成功;我们将通过以下方式检验这一假设： 使用偏微分的基于试剂的模型研究体内、体外和计算机模拟梯度 反应扩散方程这些目标，加上在哺乳动物模型中的验证，将产生新的 深入了解CTC集群适应性发展的动态过程， 黑色素瘤和其他癌症的诊断、预后和治疗策略。