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

父母赠款项目3：控制乳房的因素的系统表征 癌的进展和抗药性 两个核心挑战限制了癌症疗法的有效性并实现转移：内在的发展 对靶向药物的抗性，以及通过对识别和破坏癌细胞的抗性的发展 免疫系统。传统的体外癌症模型的规模有限，并且通常缺乏关键特性 肿瘤微环境。我们最近开发了一个可扩展的癌症球体系统，该系统使得 3D文化中的第一个全基因组CRISPR屏幕；该系统中的表型更好地反映了体内肿瘤 （Han等，2020）。此外，我们制定了一种磁分离策略，以快速识别 巨噬细胞的吞噬作用（Haney等，2018），并成功扩展了该策略以研究 巨噬细胞肿瘤细胞相互作用。在这里，我们建议使用这些系统来确定 在转移性乳腺癌中对靶向和内分泌疗法的耐药性和巨噬细胞杀死。 目标1：确定高复发风险ER+乳腺癌细胞中生长和耐药性的关键驱动因素 使用CRISPRI/A屏幕的线和PDO AIM 2：系统鉴定和表征限制乳腺巨噬细胞吞噬作用的因素 癌细胞