Emerging role of tumor-derived exosomes in immune modulation and breast cancer health disparity.

肿瘤源性外泌体在免疫调节和乳腺癌健康差异中的新作用。

基本信息

批准号：
10726647
负责人：
PankaJ Chaudhary
金额：
$ 17.3万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10726647
关键词：
Accounting Actins Affect African American American Annexins Biological Models Biology Body Fluids Brain Breast Cancer Patient Breast cancer metastasis CD8-Positive T-Lymphocytes Cell Adhesion Cell Line Communication Cytoskeleton Data Depressed mood Detection Disease Disease-Free Survival Disparity Distant Distant Metastasis Endocytosis Exocytosis Extracellular Matrix Frequencies Goals Growth Factor IL6 gene Immune system In Vitro Literature Liver Location Lung Macrophage Malignant Neoplasms Mammary Gland Parenchyma Measures Mediating Mediator Membrane Molecular Natural Killer Cells Neoplasm Metastasis Non-Malignant Nucleic Acids Organ Pathway interactions Patients Peptides Plasminogen Play Population Prevention Process Prognosis Proteins Publishing Race Regulatory T-Lymphocyte Research Role STAT3 gene Sampling Serum Site Stromal Cells T-Lymphocyte TNF gene Therapeutic Tissues Transforming Growth Factor beta Tumor Necrosis Factor Ligand Superfamily Member 6 Tumor Tissue Tumor-Derived Woman angiogenesis bone breast cancer diagnosis cancer health disparity cancer subtypes caucasian American clinical translation comorbidity cytokine cytotoxic CD8 T cells exosome extracellular extracellular vesicles health care availability health care disparity humanized mouse immunoregulation improved in vivo intercellular communication malignant breast neoplasm migration mortality mouse model neoplastic cell novel novel therapeutic intervention p38 Mitogen Activated Protein Kinase peripheral blood prognostic small hairpin RNA socioeconomics stem therapeutic target therapeutically effective triple-negative invasive breast carcinoma tumor tumorigenesis

项目摘要

Project Abstract Triple-negative breast cancer (TNBC) is an aggressive and invasive breast cancer subtype, accounting for 10-15% of breast cancer diagnoses. TNBC affects African-American (AA) women three times more than Caucasian-American (CA) women. Metastasis to distant vital organs such as bone, liver, lung, and brain is the most devastating feature of TNBC in AA women. Tumor-derived exosomes are mediators of aggressive distant metastasis by contributing to the establishment of a pre-metastatic niche. Therefore, it is critical to investigate the molecular mechanism(s) that drive tumor-derived exosome-mediated immune modulation and pre- metastatic niche formation for aggressive metastasis in TNBC. Annexin A2 (AnxA2) is an often identified exosomal protein with elevated levels in TNBC patient sera and cell lines. The higher expression of exosomal AnxA2 (exo-AnxA2) in serum samples is associated with poor overall survival and poor disease-free survival in breast cancer patients. In addition, the expression of serum exo-AnxA2 is significantly high in AA women with TNBC and promotes angiogenesis. Our data suggest a role for Exo-AnxA2 in establishing a pre- metastatic niche by immune modulation, which subsequently promotes TNBC metastasis. The goal of our research is to develop improved therapeutic options for TNBC. We hypothesize that high expression of Exo- AnxA2 plays a vital role in immune modulation at the pre-metastatic niche, thereby promoting TNBC metastasis. We will address this hypothesis by the following two specific aims: Aim 1: Determine the mechanism(s) that drive exo-AnxA2-mediated immune modulation and metastatic niche formation for aggressive metastasis in breast cancer. Aim 2: Determine the role of patient-derived exo-AnxA2 with measures of disease aggressiveness among racially distinct populations of TNBC patients using humanized mouse model system. We predict that high concentrations of exo-AnxA2 in the sera of TNBC patients will be shown to contribute to the aggressive biology of this disease, especially in AA women, by immune modulation at the pre-metastatic niche site.

项目摘要三阴性乳腺癌（TNBC）是一种侵袭性和侵袭性乳腺癌亚型，占 10-15% 的乳腺癌诊断。 TNBC 对非裔美国 (AA) 女性的影响是女性的三倍美国白人 (CA) 女性。远处重要器官（如骨、肝、肺、脑）的转移是 TNBC 对 AA 女性最具破坏性的特征。肿瘤来源的外泌体是侵袭性远处转移的介质通过促进转移前生态位的建立来促进转移。因此，调查至关重要驱动肿瘤源性外泌体介导的免疫调节和预免疫的分子机制 TNBC 侵袭性转移的转移生态位形成。膜联蛋白 A2 (AnxA2) 是一种经常被识别的 TNBC 患者血清和细胞系中外泌体蛋白水平升高。外泌体表达量较高血清样本中的 AnxA2 (exo-AnxA2) 与较差的总生存率和较差的无病生存率相关在乳腺癌患者中。此外，AA女性血清中exo-AnxA2的表达显着升高与 TNBC 结合并促进血管生成。我们的数据表明 Exo-AnxA2 在建立预- 通过免疫调节形成转移生态位，随后促进 TNBC 转移。我们的目标研究的目的是开发改进的 TNBC 治疗方案。我们假设Exo-的高表达 AnxA2 在转移前生态位的免疫调节中发挥着至关重要的作用，从而促进 TNBC 转移。我们将通过以下两个具体目标来解决这一假设：目标 1：确定驱动 exo-AnxA2 介导的免疫调节和转移生态位形成的机制乳腺癌的侵袭性转移。目标 2：确定患者来源的 exo-AnxA2 的作用使用人源化方法测量 TNBC 患者不同种族群体中的疾病侵袭性小鼠模型系统。我们预测 TNBC 患者血清中的高浓度 exo-AnxA2 将研究表明，通过免疫调节，尤其是在 AA 女性中，该疾病会导致这种疾病的侵袭性生物学在转移前的利基位点。