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）是一种侵略性亚型，患者表现出广泛的肿瘤内 基因组异质性，经常（50％）发展对新辅助化疗（NAC）的抗性 导致转移性疾病和死亡。由于没有激素受体和靶向疗法， TNBC患有难治性疾病的患者通常保留有限的治疗选择。目前，我们的理解 肿瘤细胞的基因组进化以及肿瘤微环境在化学疾病中的作用 在原始和转移器官，该提案旨在解决的知识上是一个重大差距。 我们的小组开发了可以克服的尖端单细胞DNA和RNA测序技术 以前的技术障碍和局限 肿瘤细胞对化学疗法的表型演化。我们的初步数据以少数数量 TNBC患者表明，化学抗性的基因组演化是通过自适应选择的 预先存在的突变和拷贝数变化，然后是转录重编程， 达到化学抗性表型（Kim等人，2018，细胞）。我们进一步假设该转录 重新编程肿瘤微环境中的细胞类型发生在化学抗性疾病中，并且 电阻程序是在遥远的转移器官位点克隆遗传的。全面调查 在大型新辅助化疗中，TNBC患者的纵向样本中的这些问题 试验（Artemis），我们提出了三个协同目标：AIM 1将确定拷贝数畸变（CNAS）是否是否 与化学抗性有关 接受治疗。 AIM 2将研究微环境中的肿瘤细胞和细胞类型是否经历转录 在难治性疾病中重新编程。 AIM 3将确定原发性抗性细胞的亚群是否 肿瘤种子在远处器官部位的转移性病变和抗性程序。这些完成 AIMS将定义TNBC患者化学耐药性的基因组和进化基础，并将提供新的 克服化学抗性疾病的诊断生物标志物和治疗靶标，这是一个关键的未得到 临床需求。我们的长期目标是将单细胞测序技术转化为诊所 准备对乳腺癌患者的诊断和治疗产生重大影响。提议 目标与NIH的使命直接保持一致，以减少发病率并改善乳房的生活质量 癌症患者。