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

基本信息

批准号：
10471185
负责人：
Richard Mark White
金额：
$ 61.91万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10471185
关键词：
Address Advanced Malignant Neoplasm Affect Animals Apoptosis Automobile Driving Blood Blood Circulation Cancer Etiology Cell Line Cells Cessation of life 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 clinical prognosis 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

项目摘要

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（晚期癌症的定义特征）通常代表从可治愈到无法治愈的过渡疾病。转移性级联反应包括一系列癌细胞必须克服的严重障碍，每个都高效且显然是随机的；我们目前无法预测是否，何时何地发生转移的地方。我们建议将生态晶状体应用于转移。具体来说，我们会的研究推动循环肿瘤细胞（CTC）簇的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结合黑色素瘤。黑色素瘤是最致命的皮肤癌，在局部疾病与转移性疾病的患者的结局：血液中CTC簇患者的结局更糟临床预后。尽管它们的重要性，但CTC群集形成的基础机制，增加了转移能力和治疗靶向的潜力仍然是在黑色素瘤中尤其了解的。我们利用转移性黑色素瘤的斑马鱼模型，包括能够将其移植到透明的卡斯珀斑马鱼中，它提供了一个强大的系统来定量研究CTC簇从生态学增加的转移潜力增加的机制看法。我们的三个具体目的解决了CTC簇与转移性健身的关系：（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；我们将使用数学模型检验这一假设以预测黑色素瘤簇的成功如何随尺寸而变化，我们将与斑马鱼数据面对这些模型量化黑色素瘤CTC簇的转移性健身景观；然后，我们将引入遗传对群体内部合作的假设机制的扰动，并阐明簇健身景观形状的基础机制。（目标2）我们假设高度内部簇多样性促进总体转移性健身dospite的存在健康;我们将通过具有黑色素瘤特异性形式的通用形式的工程簇来检验这一假设异质性；我们将应用定量统计分析来比较高多样性群集移植到斑马鱼中并评估复合异质性在CTC群集转移性中的作用使用多层次选择理论的健身。（目标3）我们假设该微环境梯度扩散的物质决定了分块细胞簇的成功。我们将通过使用具有部分差异的基于代理的模型在体内，体外和计算机中研究梯度反应扩散方程。这些目标，再加上哺乳动物模型中的验证，将产生新的洞悉CTC群集适应性的动态过程，以发展新的黑色素瘤和其他癌症中的诊断，预后和治疗策略。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Shifting the focus of zebrafish toward a model of the tumor microenvironment.

DOI：
10.7554/elife.69703
发表时间：
2022-12-20
期刊：
ELIFE
影响因子：
7.7
作者：
Weiss, Joshua M.;Lumaquin-Yin, Dianne;Montal, Emily;Suresh, Shruthy;Leonhardt, Carl S.;White, Richard M.
通讯作者：
White, Richard M.

Optimal Strategy and Benefit of Pulsed Therapy Depend On Tumor Heterogeneity and Aggressiveness at Time of Treatment Initiation.