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。

• 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
• 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

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）是一种侵略性和侵入性的乳腺癌亚型 10-15％的乳腺癌诊断。 TNBC影响非裔美国人（AA）女性，是 高加索裔美国人（CA）妇女。转移到远处的重要器官，例如骨，肝，肺和大脑是 TNBC在AA妇女中最具破坏性的特征。肿瘤来源的外泌体是侵略性远处的介体 转移通过为建立一种前转移的利基市场做出贡献。因此，调查至关重要 驱动肿瘤衍生的外泌体介导的免疫调节和前肿瘤的分子机制 TNBC中侵袭性转移的转移性生态位形成。 Annexin A2（Anxa2）是经常被确定的 TNBC患者血清和细胞系中水平升高的外泌体蛋白质。外泌体的较高表达 血清样品中的AnxA2（Exo-Anxa2）与总生存率差和无病生存率差有关 在乳腺癌患者中。此外，AA女性的血清exo-Anxa2的表达显着高 使用TNBC并促进血管生成。我们的数据表明exo-anxa2在建立前 免疫调节的转移性细分市场，随后促进TNBC转移。我们的目标 研究是为了为TNBC开发改进的治疗选择。我们假设exo-高表达 AnxA2在质量前生态位的免疫调节中起着至关重要的作用，从而促进了TNBC 转移。我们将通过以下两个具体目的来解决这一假设：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 乳腺癌的侵略性转移。目标2：确定患者衍生的Exo-Anxa2的作用 使用人源化的TNBC患者种族不同种群种群中疾病侵略性的措施 鼠标模型系统。我们预测，TNBC患者血清中高浓度的Exo-Anxa2将是 证明可以通过免疫调节来促进这种疾病的侵略性生物学，尤其是在AA妇女中 在移位前的利基网站上。