DELINEATING THE EVOLUTION AND ECOLOGY OF CHEMORESISTANCE IN BREAST CANCER WITH SINGLE CELL GENOMICS

用单细胞基因组学描绘乳腺癌化疗耐药性的进化和生态学

• 批准号: 10310413
• 负责人: Nicholas Navin
• 金额: $ 36.32万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310413
• 关键词: Address; Aftercare; Biopsy; Breast Cancer Patient; Breast Cancer Treatment; CRISPR/Cas technology; Cell Line; Cells; Cessation of life; Chemoresistance; Clinic; Clinical; DNA; DNA sequencing; Data; Data Set; Diagnosis; Disease; Disease Resistance; Distant; Ecology; Evolution; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genomics; Genotype; Goals; Grant; Heterogeneity; Hormonal; Human; In Vitro; Inherited; Knowledge; Left; Metastatic to; Methods; Mission; Modeling; Morbidity - disease rate; Mutation; Neoadjuvant Therapy; Neoplasm Metastasis; Organ; Outcome; Patient Care; Patients; Phenotype; Primary Neoplasm; Quality of life; RNA; Refractory Disease; Resistance; Resistance development; Role; Sampling; Seeds; Signal Pathway; Site; Stromal Cells; Technology; The Cancer Genome Atlas; Therapeutic; Time; Tissue Sample; Translating; United States National Institutes of Health; base; cell type; chemotherapy; clinical application; cohort; diagnostic biomarker; diagnostic technologies; genetic signature; improved; knock-down; malignant breast neoplasm; neoplastic cell; new therapeutic target; novel diagnostics; overexpression; programs; receptor; response; single cell sequencing; single cell technology; single-cell RNA sequencing; targeted biomarker; targeted treatment; therapeutic target; transcriptional reprogramming; transcriptome sequencing; transcriptomics; treatment response; triple-negative invasive breast carcinoma; tumor; tumor microenvironment

PROJECT SUMMARY Triple-negative breast cancer (TNBC) is an aggressive subtype in which patients display extensive intratumor genomic heterogeneity and frequently (50%) develop resistance to neoadjuvant chemotherapy (NAC) which leads to metastatic disease and death. Due to the absence of hormonal receptors and targeted therapies, TNBC patients with refractory disease are often left with limited treatment options. Currently, our understanding of the genomic evolution of tumor cells and the role of the tumor microenvironment in chemoresistant disease at primary and metastatic organ sites represents a major gap in knowledge that this proposal aims to address. Our group has developed cutting-edge single cell DNA and RNA sequencing technologies that can overcome previous technical barriers and limitations with `bulk' genomic methods for studying the genomic and phenotypic evolution of tumor cells in response to chemotherapy. Our preliminary data in a small number of TNBC patients suggests that genomic evolution of chemoresistance occurs through the adaptive selection of pre-existing mutations and copy number alterations, which is followed by transcriptional reprogramming, to achieve a chemoresistant phenotype (Kim et al. 2018, Cell). We further hypothesize that transcriptional reprogramming of cell types in the tumor microenvironment occurs in chemoresistant disease and that resistance programs are clonally inherited at distant metastatic organ sites. To comprehensively investigate these questions in matched longitudinal samples from TNBC patients in a large neoadjuvant chemotherapy trial (ARTEMIS), we propose three synergistic aims: Aim 1 will determine if copy number aberrations (CNAs) and subclonal mutations associated with chemoresistance are pre-existing and adaptively selected in response to therapy. Aim 2 will investigate if tumor cells and cell types in the microenvironment undergo transcriptional reprogramming in refractory disease. Aim 3 will determine if subpopulations of resistant cells in the primary tumor seed the metastatic lesions and confer resistance programs at distant organ sites. Completion of these aims will define the genomic and evolutionary basis of chemoresistance in TNBC patients and will provide new diagnostic biomarkers and therapeutic targets for overcoming chemoresistant disease, which is a critical unmet clinical need. Our long-term goal is to translate single cell sequencing technologies into the clinic, where they are poised to have a major impact on the diagnosis and treatment of 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.

项目概要 三阴性乳腺癌 (TNBC) 是一种侵袭性亚型，患者表现出广泛的瘤内病变 基因组异质性，并且经常（50%）对新辅助化疗（NAC）产生耐药性，这 导致转移性疾病和死亡。由于缺乏激素受体和靶向治疗， 患有难治性疾病的 TNBC 患者的治疗选择往往有限。目前，我们的了解 肿瘤细胞的基因组进化以及肿瘤微环境在化疗耐药性疾病中的作用 原发性和转移性器官部位的检测存在重大知识空白，而本提案旨在解决这一问题。 我们的团队开发了尖端的单细胞 DNA 和 RNA 测序技术，可以克服 以前用于研究基因组和基因组的“批量”基因组方法的技术障碍和限制 肿瘤细胞响应化疗的表型进化。我们的初步数据是少量的 TNBC 患者表明化学耐药性的基因组进化是通过适应性选择发生的 预先存在的突变和拷贝数改变，然后进行转录重编程，以 实现化学抗性表型（Kim et al. 2018，Cell）。我们进一步假设转录 肿瘤微环境中细胞类型的重新编程发生在化疗耐药性疾病中，并且 耐药程序在远处转移器官部位克隆遗传。为全面调查 这些问题是在大型新辅助化疗中 TNBC 患者的匹配纵向样本中提出的 试验（ARTEMIS）中，我们提出了三个协同目标： 目标 1 将确定拷贝数畸变（CNA）是否存在 与化疗耐药相关的亚克隆突变是预先存在的，并且是适应性选择的响应 来治疗。目标 2 将研究微环境中的肿瘤细胞和细胞类型是否经历转录 难治性疾病中的重编程。目标 3 将确定原代细胞中是否存在耐药细胞亚群 肿瘤播散转移性病灶并在远处器官部位赋予抵抗程序。完成这些 目标将确定 TNBC 患者化疗耐药的基因组和进化基础，并将提供新的 克服耐药性疾病的诊断生物标志物和治疗靶点，这是一个关键的未满足的问题 临床需要。我们的长期目标是将单细胞测序技术转化为临床应用 有望对乳腺癌患者的诊断和治疗产生重大影响。拟议的 目标与 NIH 降低乳腺癌发病率和提高生活质量的使命直接一致 癌症患者。