Investigating serum exosomal annexin A2 in promoting aggressive TNBC in African American women

研究血清外泌体膜联蛋白 A2 在促进非洲裔美国女性侵袭性 TNBC 中的作用

• 批准号: 10001985
• 负责人: JAMBOOR K. VISHWANATHA
• 金额: $ 36.71万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001985
• 关键词: Actins; Address; Adhesions; Affect; African; African American; Annexins; Biological Assay; Blinded; Brain; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Breast cancer metastasis; Caucasians; Cell Line; Cells; Clinical; Communication; Data; Dependence; Detection; Diagnosis; Disease; Distant; European; Extracellular Matrix; Ghana; Goals; Growth Factor; Hospitals; Immunologics; Lead; Literature; Location; Lung; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Molecular; Mus; Neoplasm Metastasis; Nigeria; Norway; Nucleic Acids; Organ; Outcome; Pathogenesis; Patients; Peptides; Plasminogen; Population; Proteins; Proteomics; Publishing; Research; Role; Serum; Signal Transduction; Site; Stromal Cells; Stromal Neoplasm; Therapeutic; Time; Tissues; Tropism; Tumor-Derived; United Kingdom; Vesicle; Woman; angiogenesis; bone; cancer cell; caucasian American; cell motility; clinical translation; cytokine; exosome; extracellular; health disparity; improved; in vivo; innovation; intercellular communication; loss of function; mortality; neoplastic cell; novel; novel therapeutics; outcome forecast; prognostic; signature molecule; small hairpin RNA; stem; targeted agent; therapeutic target; tool; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; tumorigenesis

Project Abstract Triple negative breast cancer (TNBC) affects women of African descent three times more than women of European descent. African American women with TNBC have poor survival and high mortality rates. Metastasis to distant vital organs such as bone, lung, and brain is the most devastating feature of TNBC. It is critical to investigate the molecular mechanism(s) that lead to aggressive disease in patients with TNBC so that improved therapeutic options can be developed. Emerging evidence suggests that tumor-derived exosomes are mediators of tumorigenesis and tissue-specific metastasis by contributing to the establishment of a pre- metastatic niche. Annexin A2 (AnxA2) is an often identified exosomal protein whose elevated levels are seen in TNBC patient sera and cell lines. Exosomal AnxA2 (exo-AnxA2) is more highly expressed in African American (AA) TNBC patients than in Caucasian TNBC patients resulting in reduced survival. Our recent data suggest a role for exo-AnxA2 in establishing a pre-metastatic niche which subsequently promotes breast cancer metastasis. The long-term goal of our research is to develop improved therapeutic options for aggressive TNBC that disproportionately affects AA patients. Our hypothesis for the proposed studies is that exo-AnxA2 is a determinant of the aggressiveness of TNBC metastasis and contributes to poor prognosis in AA patients with TNBC. The premise for this hypothesis stems from the literature (2, 6-9,11) and our published data indicating that exo-AnxA2 creates a pre-metastatic niche that may drive aggressive TNBC metastasis. We will address this hypothesis by the following three specific aims: Aim 1: Evaluate differences in the association of exo-AnxA2 expression with measures of disease aggressiveness among racially distinct populations. Aim 2: Determine whether exo-AnxA2 promotes aggressive TNBC metastasis. Aim 3: Determine the mechanism(s) that drives exo-AnxA2-mediated metastatic niche formation and aggressive tumors in TNBC. The impact of the proposed studies is the likely identification of a novel secreted and exosomal protein as a functional regulator of long-range communications between metastatic tumors and the target stromal microenvironment. Moreover, due to their extracellular location, secreted AnxA2 and partner proteins represent potential prognostic agents and therapeutic targets. Thus, we expect this research to open up exciting new avenues of clinical translation in metastasis detection, prognosis, and therapy for TNBC patients.

项目摘要 三重阴性乳腺癌（TNBC）影响非洲血统的女性是女性的三倍 欧洲下降。 TNBC的非洲裔美国妇女生存率较差，死亡率高。 转移到遥远的重要器官，例如骨骼，肺和大脑是TNBC最具破坏性的特征。这是 研究导致TNBC患者侵袭性疾病的分子机制至关重要 可以开发改进的治疗选择。新兴证据表明肿瘤衍生的外泌体 是肿瘤发生和组织特异性转移的介体，通过建立前 转移性利基。膜联蛋白A2（Anxa2）是一种经常被鉴定出的外泌体蛋白，可见升高的水平 在TNBC患者血清和细胞系中。外泌体anxa2（exo-anxa2）在非洲人中更高表达 美国（AA）TNBC患者比白人TNBC患者的生存率降低。我们最近的数据 提出exo-anxa2在建立一种前转移的小众市场中的作用，随后促进乳房 癌症转移。我们研究的长期目标是开发改进的治疗选择 积极影响AA患者的积极性TNBC。我们对拟议研究的假设是 exo-anxa2是TNBC转移侵略性的决定因素，导致预后不良 AA患有TNBC的患者。该假设的前提源于文献（2，6-9,11），我们已发表 数据表明exo-anxa2会产生一个可能驱动侵略性TNBC转移的te-metanclastic thee。 我们将通过以下三个特定目的来解决这一假设：目标1：评估差异 exo-anxa2表达与种族不同的疾病侵略性的衡量 人群。目标2：确定exo-anxa2是否促进了侵略性TNBC转移。目标3：确定 驱动Exo-Anxa2介导的转移性生态位形成和侵袭性肿瘤的机制 TNBC。拟议的研究的影响是可能鉴定出一种新型分泌和外泌体蛋白 作为转移性肿瘤与靶基质之间远程通信的功能调节剂 微环境。此外，由于其细胞外位置，分泌的Anxa2和伴侣蛋白代表 潜在的预后剂和治疗靶标。因此，我们希望这项研究能够打开令人兴奋的新 TNBC患者的转移检测，预后和治疗中临床翻译的途径。