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

家长资助项目3的总结：控制乳房的因素的系统表征

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