Core 2: Stanford Breast Metastasis Center Organoid Core

核心 2：斯坦福乳腺转移中心类器官核心

基本信息

批准号：
10704695
负责人：
CALVIN J KUO
金额：
$ 18.94万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-14 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10704695
关键词：
3-Dimensional Address Air Breast Breast Cancer Model Breast Cancer Patient Breast cancer metastasis CRISPR interference CRISPR-mediated transcriptional activation CRISPR/Cas technology Cancer Biology Cancer Relapse Carcinoma Cell Communication Cell Line Cells Characteristics Clinical Clinical Pathology Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Communication Consent Cryopreservation Development Disease Drug Modelings Drug Targeting Drug resistance Epithelial Cells Epithelium Experimental Models Feedback Genes Genetic Genetic Engineering Genomics Goals Heterogeneity Histologic Histology Human Immune Immune Evasion Immunological Models Impairment Information Dissemination Liquid substance Macrophage Malignant Epithelial Cell Malignant Neoplasms Mediating Metastatic breast cancer Methods Modeling Mus Mycoplasma Neoplasm Metastasis Occupational activity of managing finances Organoids Pathology Patients Pattern Phagocytosis Pharmaceutical Preparations Physiological Population Positioning Attribute Primary Neoplasm Production Property Proteomics Protocols documentation Qualifying Quality Control Research Research Personnel Resources Services Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Standardization Study models System Technology Testing Tissues Tumor Tissue Work anticancer research biobank breast cancer genomics cancer subtypes cell type digital functional genomics genome sequencing glycosylation in vitro Model malignant breast neoplasm mammary molecular subtypes nano-string next generation novel patient derived xenograft model reconstitution response single-cell RNA sequencing synergism therapeutic target therapy resistant tool transcriptome tumor tumor microenvironment tumor-immune system interactions whole genome

项目摘要

Abstract/Project Summary Breast cancer research is substantially hampered by lack of experimental models that efficiently reflect physiological disease necessary to provide a comprehensive understanding of metastatic disease. Conventional cell lines and PDX models have contributed greatly to our understanding of breast cancer biology, but are inefficiently derived, do not fully capture the heterogeneity across breast cancer subtypes and rarely mimic clinical observations. Advancements in 3D organoid models from our lab and others have shown that patient- derived organoids (PDOs) can be generated efficiently, retain histologic and genetic features of originating tumor, closely mimic patient drug response and are amendable to scale for genomic functional screens. Recently, the Kuo lab developed next generation PDOs by developing an Air-Liquid Interface (ALI) culture system that enables culture of tumor epithelium en bloc with endogenous immune stroma (Cell, 2018). The advent of ALI organoid culture provides critical experimental models for studying the tumor microenvironment. Here, the Organoid Core provides essential patient derived organoid models for identifying the evolutionary dynamics and microenvironmental determinants of metastatic breast cancer for Stanford Breast Metastasis Center investigators. Co-led by breast cancer genomics expert Dr. Christina Curtis and organoid pioneer Dr. Calvin Kuo, the Stanford Breast Metastasis Center Organoid Core is uniquely positioned and qualified to address the unmet needs highlighted in this RFA: Metastasis Research Network, by providing novel experimental models to study metastatic dissemination patterns, cellular microenvironment crosstalk, and drug response. Here, the organoid core will provide patient-derived breast cancer submerged organoids from primary and metastatic tissue to study targeted drug resistance and to define specific metastatic patterns of breast cancer sub-clones in Project 1, along with genomic functional screens using CRISPR/CAS9 and macrophage-mediated phagocytosis in Project 3. Novel human breast cancer ALI organoid models will be extensively characterized as compared to originating tissue in collaboration with Projects 1 and 2. Further, ALI culture conditions will be optimized for functional tumor-immune crosstalk studies with Project 3. Upon successful completion, novel organoid models will provide critical experimental tools for defining metastatic driver genes and identifying therapeutic targets to overcome drug resistance and immune evasion.

摘要/项目摘要由于缺乏有效反映的实验模型，乳腺癌研究受到了极大的阻碍对转移性疾病的全面理解所需的生理疾病。传统的细胞系和PDX模型为我们对乳腺癌生物学的理解做出了巨大贡献，但是效率低下，请勿完全捕获乳腺癌亚型的异质性，并且很少模仿临床观察。我们实验室和其他人的3D器官模型的进步表明，患者 - 衍生的类器官（PDOS）可以有效地产生，保留起源肿瘤的组织学和遗传特征，紧密模仿患者药物反应，并且可以对基因组功能筛查的规模进行修正。最近， Kuo Lab通过开发一个可以实现的空气界面（ALI）培养系统开发了下一代PDO 内源性免疫基质的肿瘤上皮培养（Cell，2018）。 Ali Ordanoid的出现培养提供了研究肿瘤微环境的关键实验模型。在这里，类器官核心提供必要的患者衍生的器官模型，以识别进化动力学和斯坦福乳房转移中心转移性乳腺癌的微环境决定因素调查人员。由乳腺癌基因组学专家克里斯蒂娜·柯蒂斯（Christina Curtis）博士和Organoid Pioneer博士共同领导，Calvin Kuo博士，斯坦福大学乳房转移中心类核心核心的位置独特，有资格解决在此RFA：转移研究网络中未满足的需求，通过提供新颖的实验模型研究转移性传播模式，细胞微环境串扰和药物反应。在这里， Organoid Core将提供来自原发性和转移性的患者衍生的乳腺癌淹没器官组织以研究靶向耐药性并定义乳腺癌亚基的特定转移模式在项目1中，以及使用CRISPR/CAS9和巨噬细胞介导的基因组功能屏幕项目3中的吞噬作用。新型的人类乳腺癌ALI器官模型将被广泛表征与与项目1和2合作的起源组织相比。此外，Ali培养条件将是通过项目3进行了针对功能性肿瘤 - 免疫串扰研究的优化。成功完成后，新颖器官模型将提供关键的实验工具来定义转移驱动基因并识别克服耐药性和免疫逃避的治疗靶标。