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Project 1: Modeling tumor evolution in mouse and organoid models

项目 1：在小鼠和类器官模型中模拟肿瘤进化

基本信息

批准号：
8866152
负责人：
Raul Rabadan
金额：
$ 36.64万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-19 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8866152
关键词：
Adenocarcinoma Affect Anabolism Androgen Receptor Androgens Antiandrogen Therapy Biological Biological Assay Biological Models Cells Clinic Clinical Clonal Evolution Collaborations Color Data Data Analyses Drug Targeting Epithelial Epithelium Event Evolution Gene Expression Profile Genetically Engineered Mouse Glioblastoma Growth Hematologic Neoplasms Heterogeneity Homeostasis Individual Investigation Lesion Longitudinal Studies Malignant Neoplasms Malignant neoplasm of prostate Maps Mediating Methods Modeling Molecular Mus Natural regeneration Organoids Patients Pattern Pharmaceutical Preparations Phenotype Play Prostate Prostatic Neoplasms Recording of previous events Reporter Resistance Role Sampling Severity of illness Solid Neoplasm Source Staging Stem cells Therapeutic Therapeutic Agents Tissues Treatment Failure Tumor-Associated Process Variant abiraterone base cancer initiation castration resistant prostate cancer in vivo innovation insight mathematical methods mathematical model mouse model novel receptor function recombinase response therapy resistant transcriptomics tumor tumor progression

项目摘要

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.

项目 1：在小鼠和类器官模型中模拟肿瘤进化抽象的克隆进化和肿瘤异质性被认为在产生患者特异性方面发挥着关键作用癌症进展过程中肿瘤表型的变化以及治疗耐药性的出现。尽管克隆进化在血液恶性肿瘤中已得到充分研究，但在实体瘤中的了解却较少。肿瘤，部分原因是进行纵向评估的困难。克服许多挑战在研究实体瘤中的克隆进化过程中，我们开发了一个还原论模型系统来研究克隆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以及对治疗的反应。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将使我们能够研究是否前列腺癌遵循线性或分支的进化模式。我们现在将通过追求三个具体目标来研究前列腺癌的克隆进化：1）研究通过采用多色谱系追踪和技术，研究组织稳态和再生过程中的克隆进化类器官培养以追踪克隆历史； 2) 使用多因素分析癌症进展过程中的克隆进化前列腺癌小鼠模型的颜色谱系追踪与纵向类器官培养相结合分析，通过单细胞转录组学和数学模型分析数据； 3) 调查通过药物治疗后类器官培养中克隆进化的纵向分析来评估克隆对治疗的反应治疗。进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交互进行拓扑数据分析与项目 2 和 3 一起。总之，我们提出的研究将为实体瘤克隆进化的还原论模型，提供了对耐药性出现的见解治疗。