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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

基本信息

批准号：
10704691
负责人：
MICHAEL C BASSIK
金额：
$ 34.57万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
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/10704691
关键词：
3-Dimensional Breast Breast Cancer Cell Breast Cancer Risk Factor Breast Cancer cell line CD47 gene CRISPR interference CRISPR screen CRISPR-mediated transcriptional activation Cancer Model Cancer Patient Candidate Disease Gene Cell Communication Cell Line Cells Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Dependence Development Drug Targeting Drug resistance Effectiveness Engineering Estrogen receptor positive Exhibits Fluorescent Probes Gene Combinations Gene Expression Gene Expression Profile Gene Targeting Genes Genetic Genetic Transcription Genomics Growth Immune Evasion Immune system Immunosuppression Immunotherapy In Vitro Individual Infiltration MCF10A cells MCF7 cell Macrophage Magnetism Malignant Neoplasms Mass Spectrum Analysis Measurement Measures Mediating Metastatic breast cancer Modeling Molecular Nature Neoplasm Metastasis Organoids Outcome Patients Phagocytes Phagocytosis Phenotype Post-Translational Protein Processing Process Property Proteins Proteomics Relapse Repression Resistance Resistance development Role Signal Transduction Subgroup System Testing Therapeutic Trastuzumab Tumor Escape Tumor-associated macrophages adaptive immune response anti-cancer anticancer activity biomarker driven breast cancer progression cancer cell cancer therapy candidate identification differential expression druggable target experimental study genome-wide high risk hormone therapy improved in vivo malignant breast neoplasm mammary epithelium neoplastic cell next generation novel overexpression receptor relapse risk resistance mechanism sialylation targeted treatment therapeutic target therapy resistant three dimensional cell culture transcriptomics treatment response tumor tumor initiation tumor microenvironment tumor progression tumorigenesis

项目摘要

Abstract/Project Summary Metastatic breast cancer and relapse following therapy are dependent on (1) resistance to recognition and destruction of cancer cells by the immune system, and (2) development of intrinsic resistance to targeted and endocrine therapies. The study of these processes using 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 (Nature, 2020). In addition, we developed a magnetic separation strategy to rapidly identify regulators of phagocytosis by macrophages (Nature Genetics, 2018) and have successfully extended this strategy to study macrophage-tumor cell interactions. Here we will use these systems to identify regulators of therapeutic relapse and immune evasion in metastatic breast cancer. To investigate mechanisms of relapse after therapy, we will focus on four ER+ breast cancer subgroups with high relapse risk previously identified by the Curtis Lab (Project 1). This has formed the basis of a biomarker- driven clinical trial targeting the presumed candidate drivers in these high-risk subgroups. Since the amplicons defining these subgroups each contain multiple genes, we will use functional CRISPR perturbations to test which genes (or combinations thereof) are the true drivers. Further, we will build on the comprehensive characterization of these tumors from transcriptomics (Project 1) and spatial proteomics (Project 2), adding functional measurements of the requirement for each altered factor in growth and resistance to therapy using high- throughput CRISPR screens. Together these studies will dramatically enhance our understanding of which genes are critical targets for improved therapies in high-relapse risk breast cancers. To investigate how metastatic tumors evade the immune system, we will focus on macrophage-tumor interactions. Surprisingly, although macrophages comprise 50% of the cell mass of some tumors, breast cancer cells appear resistant to macrophage killing. This is largely due to anti-phagocytic signals expressed by cancer cells, including CD47; however, accumulating evidence points to the existence of additional, unidentified anti-phagocytic signals in breast cancer. In addition, tumor-associated macrophages (TAM) are re-wired to support tumor development and have reduced phagocytosis. It remains unclear, however, which genes mediate resistance to phagocytosis in high-risk IC subtypes, and which macrophage genes underlie immunosuppression by metastatic breast cancers. Here, we will systematically identify genes limiting anti-cancer activity by macrophages by conducting CRISPR screens in both macrophages and cancer cells, making use of sophisticated ALI patient-derived organoid models to validate hits. These complementary approaches will functionally define breast cancer driver genes and therapeutic targets that control therapeutic response and immune evasion, informing the next generation of clinical trials.

抽象/项目总结