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: 10530618
• 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/10530618
• 关键词: Address; Adjuvant Chemotherapy; Aftercare; Biopsy; Breast Cancer Patient; Breast Cancer Treatment; CRISPR/Cas technology; Cell Line; Cell Reprogramming; Cells; Cessation of life; Chemoresistance; Classification; 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; 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; Signal Pathway; Site; Stromal Cells; Technology; The Cancer Genome Atlas; Therapeutic; Therapy trial; Time; Tissue Sample; Translating; United States National Institutes of Health; 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 treatment; therapeutic biomarker; 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.

项目摘要 三阴性乳腺癌（TNBC）是一种侵袭性亚型，其中患者显示广泛的瘤内肿瘤， 基因组异质性，并且经常（50%）对新辅助化疗（NAC）产生耐药性， 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患者通常只有有限的治疗选择。目前，我们的理解 肿瘤细胞的基因组进化和肿瘤微环境在化疗耐药疾病中的作用 原发性和转移性器官部位是本提案旨在解决的知识方面的一个主要空白。 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 以前的技术障碍和限制与“批量”基因组方法研究基因组和 肿瘤细胞对化疗反应的表型演变。我们的初步数据在少数 TNBC患者表明，化疗耐药性的基因组进化是通过适应性选择而发生的。 预先存在的突变和拷贝数改变，随后是转录重编程， 实现耐药性表型（Kim et al. 2018，Cell）。我们进一步假设， 肿瘤微环境中细胞类型的重编程发生在化学抗性疾病中， 耐药程序在远处转移器官部位克隆遗传。全面排查 这些问题在一个大型新辅助化疗中来自TNBC患者的匹配纵向样本中 试验（ARTEMIS），我们提出了三个协同目标：目标1将确定是否拷贝数畸变（CNAs） 与化疗耐药性相关的亚克隆突变是预先存在的， 接受治疗目的2将研究微环境中的肿瘤细胞和细胞类型是否发生转录， 重编程在难治性疾病中的应用目的3将确定原代细胞中的抗性细胞亚群是否 肿瘤播种转移病灶并在远处器官部位赋予耐药程序。完成这些 目标将定义TNBC患者化疗耐药性的基因组和进化基础，并将提供新的 诊断生物标志物和治疗靶点，以克服耐药性疾病，这是一个关键的未满足的 临床需要我们的长期目标是将单细胞测序技术应用于临床， 有望对乳腺癌患者的诊断和治疗产生重大影响。拟议 目标与NIH的使命直接一致，即降低乳腺癌的发病率并改善其生活质量 癌症患者。