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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建立肿瘤进化模型