Arp2/3 complex heterogeneity as a target for metastatic cancer

Arp2/3 复合体异质性作为转移性癌症的靶标

• 批准号: 10460277
• 负责人: PRACHEE AVASTHI
• 金额: $ 26.24万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2021-08-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460277
• 关键词: ANGPTL2 gene; Actins; Address; Affect; Area; Basement membrane; Binding; Biochemical; Biochemistry; Biological Assay; Biological Models; Blood; Breast Cancer Cell; Breast Cancer cell line; Cancer cell line; Cell Nucleus; Cell physiology; Cells; Centers of Research Excellence; Chlamydomonas; Chlamydomonas reinhardtii; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Colorectal Cancer; Complex; Core Facility; Cytoplasmic Vesicles; Cytoskeleton; Disseminated Malignant Neoplasm; Distant; Double Strand Break Repair; Endocytosis; Epithelium; Eukaryota; Extracellular Matrix; Extravasation; Fluorescence Microscopy; Future; Genes; Genetic Transcription; Goals; Green Algae; Growth; Head and Neck Squamous Cell Carcinoma; Heterogeneity; Human; Immunocompromised Host; In Vitro; Institutes; Investigation; Knowledge; Laboratories; Lymph; Malignant Neoplasms; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Mediating; Mentors; Mesenchymal; Messenger RNA; MicroRNAs; Microfilaments; Microscopy; Microtubules; Molecular; Mus; Nature; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Normal Cell; Nuclear; Pathologic; Phenotype; Play; Primary Neoplasm; Property; Protein Isoforms; Proteins; Regulation; Renal Cell Carcinoma; Role; Site; Structure; Surface; System; Testing; Tissues; Travel; Tumor Cell Invasion; Up-Regulation; Work; base; cancer cell; cell motility; circulating cancer cell; experience; experimental study; gene product; in vivo; knock-down; malignant breast neoplasm; metastatic process; migration; neoplastic cell; polymerization; protein complex; triple-negative invasive breast carcinoma; tumor progression

During metastasis, cancer cells can break free from primary tumor sites and migrate into the extracellular matrix, through the basement membrane, travel in the blood or lymph, and settle in distant sites. Actin reorganization, specifically in branched actin networks at the leading edge, is responsible for cell motility at various stages of these metastatic processes. A seven-protein complex called the Arp2/3 complex is responsible for the new actin filament growth and branching at the leading edge required for motility and proteins in this complex are often upregulated in cancer. In addition to this transcriptional upregulation, microRNAs can also control expression Arp2/3 complex components, affecting migratory potential. One protein in particular, ARPC5, is known to be regulated transcriptionally and by miRNAs in many cancers including head and neck squamous cell carcinoma, non-small cell lung cancer, bladder cancer, colorectal cancer, breast cancer, renal cell carcinoma, and prostate cancer, suggesting its key role in cancer cell migration. Given the endogenous suppression of expression by miRNAs and also the possible expression of an alternate isoform of ARPC5, ARPC5L, we propose that Arp2/3 complexes with no ARPC5, ARPC5, or ARPC5L can create versions of the actin-binding complex that are tuned for various cell functions. To address this, in Aim 1, we will purify and perform in vitro and in vivo characterization of complexes from a model system that naturally lacks ARPC5, a green alga that performs other typical Arp2/3 functions outside of surface motility. In Aim 2, we will directly test the functional consequences of ARPC5 and/or ARPC5L deletion in triple negative breast cancer cell line isolates that vary in their migration potential. Successful completion of this project will determine the molecular and cellular consequences of ARPC5-dependent Arp2/3 composition as well as the potential impact of modulating ARPC5 composition in the context of metastatic cancer. The BioMT COBRE will provide essential mentoring and collaboration from experts with decades of actin biochemistry and specifically Arp2/3 experience as well as in tumor progression. The COBRE will also provide core facility support in biochemistry and microscopy for the completion of these aims. Ultimately, this will allow the PI to expand work from her lab outside core projects in microtubule-based cytoskeletal structures into a new area of investigation related to actin regulation.

在转移过程中，癌细胞可以从原发肿瘤部位脱离并迁移到细胞外