Project 3: Systematic characterization of factors controlling breast cancer progression and resistance

项目3：控制乳腺癌进展和耐药因素的系统表征

• 批准号: 10911510
• 负责人: MICHAEL C BASSIK
• 金额: $ 6.62万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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/10911510
• 关键词: Breast Cancer Cell; Breast Cancer cell line; CRISPR interference; CRISPR screen; Cancer Model; Cell Communication; Development; Drug Targeting; Drug resistance; Effectiveness; Estrogen receptor positive; Growth; Immune system; In Vitro; Macrophage; Magnetism; Malignant Neoplasms; Metastatic breast cancer; Neoplasm Metastasis; Phagocytosis; Phenotype; Property; Resistance; Resistance development; System; breast cancer progression; cancer cell; cancer therapy; genome-wide; hormone therapy; in vivo; neoplastic cell; parent grant; relapse risk; targeted treatment; three dimensional cell culture; tumor; tumor microenvironment

Summary of the Parent Grant Project 3: Systematic characterization of factors controlling breast cancer progression and resistance Two central challenges limit effectiveness of cancer therapies and enable metastasis: development of intrinsic resistance to targeted drugs, and development of resistance to recognition and destruction of cancer cells by the immune system. Traditional in vitro cancer models have been limited in scale and often lack key properties of the tumor microenvironment. We recently developed a scalable cancer spheroid system that enabled the first genome-wide CRISPR screens in 3D culture; phenotypes in this system much better reflect in vivo tumors (Han et al., 2020). In addition, we developed a magnetic separation strategy to rapidly identify regulators of phagocytosis by macrophages (Haney et al., 2018), and have successfully extended this strategy to study macrophage-tumor cell interactions. Here we propose to use these systems to identify regulators of resistance to targeted and endocrine therapies and macrophage killing in metastatic breast cancer. Aim 1: Identify critical drivers of growth and drug resistance in high relapse risk ER+ breast cancer cell lines and PDOs using CRISPRi/a screen Aim 2: Systematic identification and characterization of factors limiting macrophage phagocytosis of breast cancer cells

家长资助项目3：控制乳房的因素的系统表征 癌症进展与耐药性 两个主要挑战限制了癌症治疗的有效性并使转移成为可能：内源性肿瘤的发展 对靶向药物的抗药性，以及对识别和破坏癌细胞的抗药性的形成 免疫系统。传统的体外肿瘤模型规模有限，往往缺乏关键特性。 肿瘤微环境的影响。我们最近开发了一种可扩展的癌症球体系统，使 首次在3D培养中进行全基因组CRISPR筛选；该系统中的表型更好地反映了体内肿瘤 (han等人，2020)。此外，我们开发了一种磁分离策略，以快速识别 巨噬细胞的吞噬作用(Haney等人，2018年)，并成功地将这一策略扩展到研究 巨噬细胞与肿瘤细胞的相互作用。在这里，我们建议使用这些系统来识别监管机构 转移性乳腺癌对靶向和内分泌治疗及巨噬细胞杀伤的抵抗。 目的1：确定高复发风险ER+乳腺癌细胞生长和耐药的关键驱动因素 使用CRISPRi/a屏幕的线路和PDO 目的2：系统鉴定和表征乳腺巨噬细胞吞噬功能的限制因素 癌细胞