Project 1: Modeling tumor evolution in mouse and organoid models

项目1：在小鼠和器官模型中模拟肿瘤进化 摘要 克隆进化和肿瘤的异质性被认为是产生患者特异性的关键因素。 癌症进展过程中肿瘤表型的变化和治疗耐药的出现。 虽然克隆进化在血液系统恶性肿瘤中已经得到了很好的研究，但在固体中却知之甚少。 肿瘤，部分原因是难以进行纵向评估。克服许多挑战 为了研究实体肿瘤的克隆进化，我们开发了一个研究克隆的简化论模型系统。 并证明了其在前列腺癌治疗中的可行性。在初步研究中，我们证明了多色 血统追踪可以用来追踪基因工程小鼠前列腺的克隆命运 一种新的有机培养方法可用于克隆生长的纵向评估 对治疗的反应。这些方法将与单细胞转录组分析一起使用 肿瘤的异质性和复杂的数学方法将使我们能够调查 前列腺癌遵循线性或分支进化模式。 我们现在将通过追求三个特定的目标来研究前列腺癌的克隆进化：1)研究 组织动态平衡和再生过程中克隆进化的多颜色谱系追踪和 器官培养，以跟踪克隆历史；2)分析克隆进化在癌症进展过程中使用多个 前列腺癌小鼠模型的色谱学追踪及器官培养 分析，用单细胞转录学和数学模型分析数据；以及3)调查 用药物后器官培养克隆进化的纵向分析研究治疗的克隆反应 治疗。演化模空间的分析将极大地促进这些研究 与数学核心合作以及通过互动进行的拓扑数据分析 项目2和项目3。综上所述，我们建议的研究将为 实体肿瘤克隆进化的简化论模型，为出现对 心理治疗。

Project 1: Modeling tumor evolution in mouse and organoid models ABSTRACT Clonal evolution and tumor heterogeneity are believed to play key roles in generating patient-specific variations in tumor phenotype during cancer progression and in the emergence of treatment resistance. Although clonal evolution has been well studied in hematological malignancies, it is less understood in solid tumors, in part due to difficulties in performing longitudinal assessments. To overcome many of the challenges of studying clonal evolution in solid tumors, we developed a reductionist model system for investigating clonal histories and demonstrated its feasibility in prostate cancer. In preliminary studies, we show that multi-color lineage-tracing can be employed to follow clonal fates in genetically-engineered mouse models of prostate cancer, and that a novel organoid culture approach can be used for longitudinal assessments of clonal growth and response to therapy. These approaches will be used together with single-cell transcriptome analyses of tumor heterogeneity and sophisticated mathematical approaches that will allow us to investigate whether prostate cancer follows a linear or branched evolutionary pattern. We will now investigate clonal evolution in prostate cancer by pursuing three specific aims: 1) investigation of clonal evolution during tissue homeostasis and regeneration by employing multi-color lineage-tracing and organoid culture to follow clonal histories; 2) analysis of clonal evolution during cancer progression using multi- color lineage-tracing in mouse models of prostate cancer together with organoid culture for longitudinal analyses, with data analyzed by single-cell transcriptomics and mathematical modeling; and 3) investigation of the clonal response to therapy by longitudinal analyses of clonal evolution in organoid culture after drug treatments. These studies will be greatly facilitated by the analyses of evolutionary moduli spaces and topological data analyses performed in collaboration with the Mathematical Core, as well as by interactions with Projects 2 and 3. Taken together, our proposed studies will provide robust mathematical analyses of a reductionist model of clonal evolution for solid tumors, providing insights into the emergence of resistance to therapy.