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INVESTIGATING TUMOR INITIATION AND INVASION IN PREMALIGNANT BREAST CANCER WITH SPATIAL SINGLE CELL GENOMICS

利用空间单细胞基因组学研究癌前乳腺癌的肿瘤发生和侵袭

基本信息

批准号：
10627906
负责人：
Nicholas Navin
金额：
$ 35.87万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-12 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627906
关键词：
ATAC-seq Aneuploidy Atlases Basement membrane Biological Markers Breast Breast Cancer Patient Carcinoma Cell Line Cell Separation Cell Survival Cells Clinic Clinical Clinical Research Complex DNA DNA Sequence Alteration DNA sequencing Diagnosis Diagnostic Diploidy Disease Duct (organ) structure Early Diagnosis Ecosystem Endothelial Cells Epithelial Cells Event Evolution Fibroblasts Freezing Genes Genetic Transcription Genome Genomics Goals Grant Immune In Situ Lesion In Vitro Intraductal Hyperplasia Invaded Knowledge Lead Lesion Macrophage Malignant Neoplasms Mammary Neoplasms Methods Mission Modality Modeling Molecular Morbidity - disease rate Mutation Myoepithelial cell Noninfiltrating Intraductal Carcinoma Operative Surgical Procedures Patients Phenotype Process Quality of life RNA Research Personnel Resolution Role Sampling Source Spatial Distribution Stromal Cells T-Lymphocyte Technology Tissue Banks Tissues Translating Tumor Cell Invasion Tumor Promotion United States National Institutes of Health Work breast cancer progression cancer cell cancer invasiveness cell type clinical diagnostics cohort epigenomics human tissue improved infiltrating duct carcinoma malignant breast neoplasm migration neoplastic cell premalignant programs single cell sequencing single-cell RNA sequencing transcriptional reprogramming transcriptome sequencing transcriptomics tumor tumor initiation tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

PROJECT SUMMARY Ductal Carcinoma in situ (DCIS) and Atypical Ductal Hyperplasia (ADH) are the most common forms of early- stage breast cancer and are non-obligatory precursors to invasive ductal carcinoma (IDC). Genomic studies of tumor initiation and invasion in premalignant breast cancer represents a major gap in knowledge and have been challenging due to several technical barriers, including the limited number of tumor cells in the ducts, the logistical challenge of obtaining fresh or frozen tissues, and the lack of spatial resolution in standard genomic methods. To overcome these challenges, we have developed cutting-edge single cell sequencing methods to profile DNA, RNA and Epigenomics with spatial-resolution in human tissue sections. We have also established a unique fresh DCIS tissue collection program at MD Anderson to procure viable cells from DCIS patients directly after surgery for single cell sequencing to overcome logistical challenges in sample sources. In our previous work, we applied these methods to study copy number evolution during invasion in synchronous DCIS-IDC patients, which identified punctuated copy number evolution (PCNE) in the ducts and revealed a multi-clonal model of invasion (Casasent et al. 2018, Cell). This proposal will greatly extend these initial studies to study mutational, epigenomic and transcriptional reprogramming in the tumor cells and the microenvironment during premalignant breast cancer progression. Our central hypothesis is that the evolution of premalignant lesions requires initiating mutations and punctuated copy number evolution (PCNE), which is followed by transcriptional and epigenomic reprogramming in tumor cells and the microenvironment that leads to invasion. AIM1 will investigate breast tumor initiation in ADH and DCIS, while AIM2 will focus on tumor invasion in DCIS and IDC, and AIM3 will study role of the tumor microenvironment in DCIS progression. Candidate mutations identified in these aims will be functionally validated in vitro. Completion of these aims will greatly improve our fundamental knowledge of tumor initiation and invasion in premalignant breast cancer progression, which may lead to new biomarkers and diagnostic modalities for identifying ADH and DCIS patients that will progress to invasive disease and is critical unmet clinical need. Our long-term goal is to translate single cell sequencing technologies into the clinic, where they are poised to make a major impact on the diagnosis and treatment of premalignant breast cancer patients. The proposed aims are directly aligned with the mission of NIH to reduce morbidity and improve the quality of life for breast cancer patients through early detection.

项目摘要导管原位癌（DCIS）和非典型导管增生（ADH）是最常见的早期乳腺癌。分期乳腺癌，是浸润性导管癌（IDC）的非强制性前体。基因组研究癌前乳腺癌的肿瘤发生和侵袭代表了知识上的一个主要空白，由于几个技术障碍，包括导管中肿瘤细胞数量有限，获得新鲜或冷冻组织的后勤挑战，以及标准基因组学中缺乏空间分辨率，方法.为了克服这些挑战，我们开发了尖端的单细胞测序方法在人体组织切片中以空间分辨率分析DNA、RNA和表观基因组学。我们还在MD安德森建立了一个独特的新鲜DCIS组织收集程序，以从DCIS中获得活细胞患者手术后直接进行单细胞测序，以克服样品来源的后勤挑战。在我们以前的工作中，我们应用这些方法来研究在入侵过程中拷贝数的演变，同步DCIS-IDC患者，发现了导管中的间断拷贝数演变（PCNE），揭示了一种多克隆侵袭模型（Casasent et al. 2018，Cell）。这项提案将大大扩展这些研究肿瘤细胞中突变、表观基因组和转录重编程的初步研究，癌前乳腺癌进展的微环境。我们的核心假设是癌前病变的发生需要起始突变和间断拷贝数进化（PCNE），随后是肿瘤细胞中的转录和表观基因组重编程，以及导致肿瘤发生的微环境。入侵。AIM 1将研究ADH和DCIS中的乳腺肿瘤起始，而AIM 2将重点研究肿瘤 AIM 3将研究肿瘤微环境在DCIS和IDC进展中的作用。在这些目标中鉴定的候选突变将在体外进行功能验证。实现这些目标将极大地提高我们对癌前乳腺癌的肿瘤发生和侵袭的基础知识进展，这可能导致新的生物标志物和诊断模式，以确定ADH和DCIS 患者将进展为侵袭性疾病，并且是关键的未满足的临床需求。我们的长期目标是将单细胞测序技术转化为临床，在那里它们将对乳腺癌癌前病变的诊断和治疗。所提出的目标与美国国立卫生研究院的使命是通过以下措施降低乳腺癌患者的发病率并提高其生活质量：早期检测