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Molecular mechanisms underlying circulating tumor cell aggregation

循环肿瘤细胞聚集的分子机制

基本信息

批准号：
10608941
负责人：
Huiping Liu
金额：
$ 35.87万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-11 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608941
关键词：
4T1 Antibodies Binding Biochemical Bioinformatics Blocking Antibodies Blood Vessels Breast Breast Oncology Breast cancer metastasis CD44 gene CDKN1A gene Cancer Patient Cell Aggregation Cell Line Cell Survival Cell model Cells Cessation of life Circulation Clinical Data Down-Regulation Extracellular Domain Genes Goals Human Image In Vitro Individual MDA MB 231 Machine Learning Malignant Neoplasms Mammary Neoplasms Mammospheres Mediating Metastatic Neoplasm to the Lung Methods Modeling Molecular Mus Mutagenesis Neoplasm Circulating Cells Neoplasm Metastasis Oncologist Pathway interactions Patient-derived xenograft models of breast cancer Patients Phenotype Phosphotransferases Prognosis Property Proteins Research Design Role Signaling Protein Specimen Structural Biologist Technology Testing Texas Therapeutic Tumor Cell Line Tumor Promotion United States Universities Woman effective therapy human model in vivo inhibitor lung colonization lung tumorigenesis malignant breast neoplasm member migration mortality mouse model neoplastic cell new therapeutic target novel novel therapeutics overexpression patient derived xenograft model preclinical study prevent small molecule inhibitor stemness therapeutic development triple-negative invasive breast carcinoma tumor tumor initiation tumorigenesis tumorigenic

项目摘要

Circulating tumor cells (CTCs) pose continuous and persistent threats to create new metastases albeit at an unknown, extremely low efficiency. Compared to single CTCs, clusters of multicellular CTCs possess 20-100 times higher metastatic capacity, create more polyclonal metastasis, and correlate with worse prognosis. Our previous studies identified that in addition to collective migration and cohesive shedding, tumor cell aggregation is a new mechanism for CTC cluster formation, enhancing cancer stemness and polyclonal metastasis. The objectives of this proposal are to elucidate the molecular mechanisms underlying CD44 and PAK2-promoted CTC aggregation, identify the drivers of CTC cluster-mediated polyclonal metastasis, and therefore develop proof-of-principle targeting strategies to block lung metastasis of triple negative breast cancer, using multiple human PDXs and CTC lines as well as mouse tumor models. The collaborative team includes Dr. Huiping Liu (Northwestern University) with expertise in CTC and cancer stemness, breast oncologist Dr. Massimo Cristofanilli (Northwestern University), imaging expert Dr. Constadina Arvanitis (Northwestern University), and bioinformaticist and structural biologist Dr. Yang Shen (Texas A & M).

循环肿瘤细胞（CTC）造成持续和持久的威胁，以产生新的转移，尽管在一个特定的时间内，未知，效率极低。与单个CTC相比，多细胞CTC的簇具有20-100 倍高的转移能力，产生更多的多克隆转移，并与更差的预后相关。我们以前的研究表明，除了集体迁移和内聚脱落外，是CTC簇形成、增强癌症干性和多克隆转移的新机制。的本提案的目的是阐明CD 44和PAK 2促进的细胞凋亡的分子机制。 CTC聚集，确定CTC簇介导的多克隆转移的驱动因素，从而开发使用多种靶向策略来阻断三阴性乳腺癌的肺转移的原理验证人PDX和CTC系以及小鼠肿瘤模型。合作团队包括刘慧平博士（西北大学）在CTC和癌症干细胞的专业知识，乳腺肿瘤学家马西莫博士 Cristofanilli（西北大学）、成像专家Constadina Arvanitis博士（西北大学）和生物信息学家和结构生物学家Yang Shen博士（德克萨斯A & M）。