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

项目摘要 三阴性乳腺癌（TNBC）是一种侵袭性和浸润性乳腺癌亚型，占 10-15%的乳腺癌诊断。TNBC对非洲裔美国人（AA）女性的影响是 美国白人（CA）女性。转移到远处的重要器官，如骨、肝、肺和脑， 最具破坏性的特点TNBC在AA妇女。肿瘤来源的外泌体是侵袭性远处转移的介质。 通过促进转移前小生境的建立来促进转移。因此，调查 驱动肿瘤源性外泌体介导的免疫调节和预- TNBC中侵袭性转移的转移小生境形成。膜联蛋白A2（AnxA 2）是一种常见的 在TNBC患者血清和细胞系中具有升高水平的外泌体蛋白。外泌体的高表达 血清样本中的AnxA 2（exo-AnxA 2）与总生存率和无病生存率相关 在乳腺癌患者中。此外，AA妇女血清exo-AnxA 2的表达显著升高， 与TNBC和促进血管生成。我们的数据表明，Exo-AnxA 2在建立前 通过免疫调节转移小生境，其随后促进TNBC转移。我们的目标 研究的目的是为TNBC开发更好的治疗方案。我们假设高表达的外切- AnxA 2在转移前小生境的免疫调节中起着至关重要的作用，从而促进TNBC 转移我们将通过以下两个具体目标来解决这个假设：目标1：确定 驱动exo-AnxA 2介导的免疫调节和转移性小生境形成的机制， 乳腺癌的侵袭性转移目的2：确定患者来源的exo-AnxA 2与 使用人源化的TNBC患者的种族不同群体中的疾病侵袭性的测量 小鼠模型系统。我们预测，TNBC患者血清中高浓度的exo-AnxA 2将是TNBC患者的一个重要因素。 显示有助于这种疾病的侵袭性生物学，特别是在AA女性中，通过免疫调节 在转移前的小生境部位。

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.