Project 1: Modeling tumor evolution in mouse and organoid models

项目1：在小鼠和类器官模型中建模肿瘤演变 摘要 克隆进化和肿瘤异质性被认为在产生患者特异性肿瘤特异性免疫应答中起关键作用。 癌症进展期间肿瘤表型的变化和治疗抗性的出现。 尽管克隆进化在恶性血液病中已经得到了很好的研究，但在实体肿瘤中的了解较少。 肿瘤，部分原因是难以进行纵向评估。为了克服许多挑战 为了研究实体瘤中的克隆进化，我们开发了一个简化模型系统来研究克隆进化， 历史并证明了其在前列腺癌中的可行性。在初步研究中，我们表明，多色 谱系追踪可用于追踪前列腺的基因工程小鼠模型中的克隆命运 癌症，并且一种新的类器官培养方法可用于克隆生长的纵向评估 和对治疗的反应这些方法将与单细胞转录组分析一起使用， 肿瘤异质性和复杂的数学方法，使我们能够调查是否 前列腺癌遵循线性或分支的进化模式。 我们现在将通过三个具体目标来研究前列腺癌的克隆进化：1）研究 在组织稳态和再生过程中的克隆进化， 类器官培养以跟踪克隆历史; 2）使用多克隆抗体分析癌症进展期间的克隆进化。 在前列腺癌小鼠模型中的彩色谱系追踪以及类器官培养用于纵向 分析，通过单细胞转录组学和数学建模分析数据;和3）调查 通过药物后类器官培养中克隆进化纵向分析对治疗的克隆应答 治疗。演化模空间的分析将极大地促进这些研究， 与数学核心合作进行的拓扑数据分析，以及通过交互 项目2和3。总之，我们提出的研究将提供一个强大的数学分析， 实体瘤克隆进化的简化模型，提供了对 疗法

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.