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

• 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
• 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

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 非整倍体是癌细胞普遍存在的特征，据信非整倍体的积累经常发生 通过四倍化（基因组加倍）作为中间步骤。这一想法是基于以下观察， 所有肿瘤的近40%在其克隆进化期间可能经历了全基因组复制， 四倍体显示出缓冲染色体不稳定性（CIN），四倍体（4 N），而不是二倍体（2N）， 乳腺上皮细胞可诱发裸鼠皮下肿瘤。一个被广泛接受的模型表明， 在四倍化过程中通常会出现额外的中心体， 在有丝分裂期间的错误分离导致非整倍体和CIN的积累。可能的选择 由非整倍性赋予的优势反过来会促进肿瘤发生。对这一模式的支持来自 在人类肿瘤中观察到非整倍体和额外中心体， 在动物模型中，额外的中心体可促进肿瘤发生。然而，最近的报告显示， 保持在标准培养条件下的细胞自发地失去在培养期间获得的额外中心体。 四倍化，并且这种中心体丢失可以在很短的时间内发生（约两周）。的 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 条件表明体内生态小生境（例如，肿瘤微环境中的各种因素） 可以施加特定的选择压力，影响4 N细胞的进化，从而影响 四倍化这一假设将通过实验诱导四倍体，然后将 多学科的方法来研究改变倍性/中心体数目和细胞周期之间的相互作用。 三个具体研究目标的微观环境。第一个目标将决定物理学的影响， 化学微环境对4 N细胞进化的影响，并将识别特定的，生理相关的， 微环境的物理化学性质产生了一个进化的细胞群体， 在标准培养条件下出现。第二个目标将建立如何与基质细胞沟通， 影响4 N上皮细胞的进化，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具有改变的倍性的细胞的进化中。第三个目标将确定关键 在体内驱动4 N细胞进化的过程。这将通过将新形成的4 N个单元注入 小鼠模型，然后表征进化的肿瘤衍生细胞群。基于ODE的 在每个目标中将使用数学模型来捕获细胞亚群的进化动力学， 定义倍性和中心体数量，并确定事件，细胞过程和微环境 这些因素驱动着不同的、依赖于环境的、进化的结果。这些研究的结果 不仅拓宽了现有知识，而且为未来确定潜在的 分子靶点和/或新型微环境操作用于癌症治疗。