Combining modeling and experiments to study the evolution of cells with altered ploidy

结合建模和实验来研究倍性改变的细胞的进化

基本信息

批准号：
10555229
负责人：
Daniela Cimini
金额：
$ 35.18万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10555229
关键词：
3-Dimensional Affect Aneuploidy Animal Model Automobile Driving Breast Epithelial Cells Buffers Cell division Cell physiology Cells Centrosome Chemicals Chromosomal Instability Chromosomes Clonal Evolution Collagen Colorectal Cancer Communication Environment Epithelial Cells Event Evolution Exposure to Future Genome Goals Human Knowledge Lead Mitosis Modeling Molecular Target Mus Nude Mice Nutrient Organelles Outcome Ovarian Oxygen Pattern Physiological Ploidies Population Population Dynamics Process Proliferating Property Reporting Research Role Shapes Side Signaling Molecule Stromal Cells Surface System Testing Tetraploidy Time Tissues Tumor-Derived Variant cancer cell cancer therapy chromosome missegregation collagen scaffold dynamical evolution environmental stressor experimental study in vivo interdisciplinary approach intestinal epithelium mathematical model mouse model multidisciplinary neoplastic cell novel predictive modeling pressure subcutaneous tissue culture tumor tumor microenvironment tumorigenesis tumorigenic whole genome

项目摘要

Project Summary Aneuploidy is a ubiquitous feature of cancer cells, and accumulation of aneuploidy is believed to often happen via tetraploidization (genome doubling) as an intermediate step. This idea is based on the observations that nearly 40% of all tumors have likely undergone whole genome duplication during their clonal evolution, that tetraploidy was shown to buffer chromosomal instability (CIN), and that tetraploid (4N), but not diploid (2N), mammary epithelial cells could induce subcutaneous tumors in nude mice. A widely accepted model suggests that the extra centrosomes commonly arising during tetraploidization are responsible for ongoing chromosome missegregation during mitosis leading to the accumulation of aneuploidy and CIN. A possible selective advantage conferred by aneuploidy would, in turn, promote tumorigenesis. Support for this model comes from the fact that both aneuploidy and supernumerary centrosomes have been observed in human tumors and that extra centrosomes can promote tumorigenesis in animal models. However, recent reports have shown that cells kept in standard culture conditions spontaneously lose extra centrosomes acquired during tetraploidization, and that this centrosome loss can occur over a very short time period (about two weeks). The discrepancies between what is believed to happen in vivo and what is observed in standard tissue culture conditions suggests that the in vivo ecological niche (e.g., various factors within the tumor microenvironment) can impose specific selective pressures that influence the evolution of 4N cells, and thus the consequences of tetraploidization. This hypothesis will be tested by experimentally inducing tetraploidy and then combining a multi-disciplinary approach to study the interplay between altered ploidy/centrosome number and the microenvironment in three specific research aims. The first aim will determine the effects of the physico- chemical microenvironment on the evolution of 4N cells and will identify specific, physiologically relevant, physico-chemical properties of the microenvironment that produce an evolved cell population unlike the one emerging in standard culture conditions. The second aim will establish how communication with stromal cells influences the evolution of 4N epithelial cells and specifically assess the role of signaling molecules and cell- cell physical interactions in shaping the evolution of cells with altered ploidy. The third aim will identify the key processes driving the evolution of 4N cells in vivo. This will be achieved by injecting newly formed 4N cells in mouse models and then characterizing the evolved, tumor-derived cell population. An ODE-based mathematical model will be used in each aim to capture the evolution dynamics of subpopulations of cells with defined ploidies and centrosome numbers and pinpoint the events, cellular processes, and microenvironmental factors that drive the differential, context-dependent, evolutionary outcomes. The findings from these studies will not only broaden the current knowledge, but also set the stage for future identification of potential molecular targets and/or novel microenvironment manipulations for cancer therapy.

项目摘要非整倍性是癌细胞的普遍特征，据信非整倍性的积累经常发生通过四倍体化（基因组加倍）作为中间步骤。这个想法是基于观察结果在所有肿瘤中，近40％的肿瘤可能在其克隆进化过程中经历了整个基因组重复，四倍体被证明是缓冲染色体不稳定性（CIN），四倍体（4N），但不是二倍体（2n），乳腺上皮细胞可以在裸鼠中诱导皮下肿瘤。广泛接受的模型建议四倍体化期间通常出现的额外中心体负责持续的染色体有丝分裂过程中的错误分析导致非整倍性和CIN的积累。可能的选择性非整倍性赋予的优势反过来促进肿瘤发生。对此模型的支持来自在人类肿瘤中已经观察到了非整倍性和超整个中心体的事实，并且额外的中心体可以促进动物模型中的肿瘤发生。但是，最近的报告表明保存在标准培养条件下的细胞自发失去了在四倍体化，并且这种中心体损失可以在很短的时间内（大约两周）发生。这在体内发生的情况与标准组织培养中观察到的情况之间的差异条件表明，体内生态生态位（例如，肿瘤微环境中的各种因素）可以施加特定的选择性压力，以影响4N细胞的演变，从而产生的后果四倍体化。该假设将通过实验诱导四倍体进行检验，然后结合多学科的方法是研究改变倍数/中心数和中心数之间的相互作用三个特定研究目的的微环境。第一个目标将决定物理的影响化学微环境在4N细胞的演化上，并将确定特定的生理相关，微环境的物理化学特性，产生了进化的细胞种群在标准培养条件下出现。第二个目标将确定与基质细胞的沟通方式影响4N上皮细胞的演变，并特别评估信号分子和细胞的作用细胞物理相互作用在塑造细胞演变的变化时发生变化。第三个目标将确定钥匙过程驱动体内4N细胞的演变。这将通过在中注入新形成的4N细胞来实现小鼠模型，然后表征进化的肿瘤衍生细胞群。基于ODE的数学模型将用于每个目标，以捕获细胞亚群的演化动力学定义的拼字点和中心数，并查明事件，蜂窝过程和微环境驱动差异，与上下文相关的进化结果的因素。这些研究的发现不仅会扩大当前知识，而且还为未来的潜力奠定了基础分子靶标和/或新型的微环境操纵癌症治疗。