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.

项目概要转移是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转移级联由癌细胞必须克服的一系列严重障碍组成，每一个都非常低效并且显然是随机的；我们目前无法预测是否、何时以及我们建议应用生态视角来观察转移。研究驱动循环肿瘤细胞 (CTC) 簇转移潜力增加的过程通过数学建模和斑马鱼模型体内定量实验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。局部疾病患者与转移性疾病患者的结果：血液中存在 CTC 簇的患者的预后较差尽管CTC簇形成的机制很重要，但它们的临床预后却有所增加。转移能力和治疗靶向的潜力仍有待研究——特别是在黑色素瘤中。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 Casper 斑马鱼中，这提供了一个强大的系统来定量从生态学角度研究 CTC 簇转移潜力增加背后的机制我们的三个具体目标解决了 CTC 簇与转移适应性的关系：（目标 1）我们指出群体规模和数量之间的权衡（生态分散的组成部分）是关键 CTC 簇的转移形成；我们将用数学模型来测试这一假设并进行预测；黑色素瘤簇的成功如何随大小而变化，我们将用斑马鱼数据来面对这些模型为了量化黑色素瘤 CTC 簇的转移适应性，我们将引入遗传因素；对簇内细胞合作的发达机制的扰动并阐明集群适应度景观形状的潜在机制（目标 2）我们捕捉到了高内部适应性。尽管存在一些个体较低的细胞，但簇多样性促进了整体转移适应性我们将通过使用黑色素瘤特异性遗传形式的基因组来检验这一假设。异质性；我们将应用定量统计分析来比较高多样性和低多样性集群移植到斑马鱼中并评估成分异质性在 CTC 簇转移中的作用使用多级选择理论（目标 3）我们捕获了微环境梯度。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：使用基于代理的偏微分模型研究体内、体外和计算机中的梯度这些目标与哺乳动物模型中的验证相结合，将产生新的结果。深入了解 CTC 集群适应度的动态过程，以开发新的黑色素瘤和其他癌症的诊断、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）

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

脉冲治疗的最佳策略和益处取决于治疗开始时肿瘤的异质性和侵袭性。

DOI：
发表时间：
2022-05-04
期刊：
影响因子：
5.7
作者：
Mathur, Deepti;Taylor, Bradford P;Chatila, Walid K;Scher, Howard I;Schultz, Nikolaus;Razavi, Pedram;Xavier, Joao B
通讯作者：
Xavier, Joao B

BayesTME: An end-to-end method for multiscale spatial transcriptional profiling of the tissue microenvironment.

BayesTME：一种用于组织微环境多尺度空间转录分析的端到端方法。

DOI：
10.1016/j.cels.2023.06.003
发表时间：
2023-07-01
期刊：
Cell systems
影响因子：
9.3
作者：
H. Zhang;Mir;a V. Hunter;a;Jacqueline Chou;J. F. Quinn;Mingyuan Zhou;R. White;Wesley Tansey
通讯作者：
Wesley Tansey

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

将斑马鱼的焦点转向肿瘤微环境模型。