ACKR3 and CXCR4 Contributions to the Tumor Microenvironment in Breast Cancer Racial Disparities

ACKR3 和 CXCR4 对乳腺癌种族差异中肿瘤微环境的贡献

• 批准号: 10244880
• 负责人: Nicole Salazar
• 金额: $ 15.5万
• 依托单位: SAN FRANCISCO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10244880
• 关键词: Address; Affect; African American; Asians; Binding; Breast Cancer Cell; Breast Cancer Detection; Breast cancer metastasis; CXCL12 gene; CXCR4 Receptors; CXCR4 Signaling Pathway; CXCR4 gene; Cancer Biology; Cancer Cell Growth; Cell Differentiation process; Cells; Cessation of life; Characteristics; Clinical; Clinical Trials; Data; Databases; Destinations; Development; Disease; Distant; Endothelial Cells; Face; Fibroblast Growth Factor; Foundations; Funding; Genomics; Goals; Hispanics; Hormones; Immune; Immune system; In Situ; Incidence; Inflammation; Knowledge; Lead; Leukocytes; Literature; Mainstreaming; Malignant Neoplasms; Mammary Neoplasms; Metastatic breast cancer; Modeling; Molecular; Neoplasm Metastasis; Network-based; Not Hispanic or Latino; Outcome; Pathway interactions; Patients; Pattern; Population; Positioning Attribute; Preventive measure; Process; Race; Regulation; Regulator Genes; Research; Resistance; Resolution; Role; Sampling; San Francisco; Signaling Protein; Site; Stromal Cells; Students; Supporting Cell; Survival Rate; System; Testing; The Cancer Genome Atlas; Tissue Sample; Tumor Angiogenesis; Tumor Tissue; Tumor-infiltrating immune cells; Universities; Woman; base; black women; cancer cell; cancer health disparity; cancer site; cancer survival; cell type; chemokine; chemokine receptor; cytokine; density; design; differential expression; disparity elimination; enhancing factor; ethnic diversity; human tissue; improved; malignant breast neoplasm; mortality; mortality disparity; neoplastic cell; new therapeutic target; overexpression; programs; racial disparity; racial diversity; receptor; receptor expression; recruit; survival outcome; therapeutic development; transcriptomics; tumor; tumor growth; tumor microenvironment; tumor progression

PROJECT SUMMARY Breast cancer (BrCa) disparities are startling and the levels of racial disparity in metastasis and survival remain unacceptable despite advancements in BrCa screening and treatment that have led to a significant decline in BrCa related deaths. This project addresses BrCa disparities with the goal of identifying cellular and molecular characteristics that certain chemokine receptors contribute to the tumor composition, or microenvironment, across different racial groups. Chemokines and their receptors are critical in determining the metastatic destination of tumor cells by supporting tumor angiogenesis and immune cell recruitment. The chemokine receptors CXCR4 and ACKR3 are co-receptors for the chemokine CXCL12, which is critical in BrCa metastasis. CXCR4 is overexpressed in BrCa tumors and ACKR3 in the tumor vasculature. Our preliminary data indicates ACKR3 and CXCR4 are differentially expressed in opposing directions in bulk breast cancer tumor tissues from different racial groups. We also identified ACKR3 and CXCR4 to be differentially expressed in a sub-set of tumor cells, the tumor endothelial cells. The goal of this project is to elucidate the patterns of ACKR3 and CXCR4 expression in distinct tumor cell subsets and how these receptors contribute to altering the tumor’s composition and eventual dissemination in women from different racial groups. We propose two specific aims to accomplish this goal. Aim 1: Determine the ACKR3 and CXCR4 signaling pathways in BrCa from samples of different racial groups. Identifying gene regulatory networks that control expression of ACKR3 and CXCR4 in BrCa across different racial groups will indicate the contribution of these receptors to BrCa disparities. Aim 2. Identify CR expression on a single-cell level in breast tumor cell subsets from racially diverse patient tissue samples. Distinct cell population functions will be modeled, quantitatively analyzed using BrCa human tissues from different race groups, and validated by testing whether factors that enhance ACKR3 and CXCR4 activity can be reversed by blocking receptor-microenvironment interactions. These findings will reveal the cellular and molecular contributions that drive ACKR3 and CXCR4 to alter the tumor landscape in BrCa disparities, including the tumor vasculature in situ and potentially at metastatic sites. Knowing these molecular features will have far-reaching implications for therapeutic development, better clinical trial development, and ultimately alleviate cancer disparities. In addition, it will enable the PI to develop her research program, gather preliminary data to seek mainstream funding and allow her to offer and engage the ethnically diverse student population at San Francisco State University, including 43% under-represented students, in exciting opportunities to conduct cancer biology research and prepare them to face the challenges of combatting cancer disparities.

项目摘要 乳腺癌（BRCA）差异开始，转移和生存的种族差异仍然存在 BRCA筛查和治疗中无法接受的目的地进步，导致大幅下降 与BRCA有关的死亡。该项目解决了BRCA分布，目的是识别细胞和分子 某些趋化因子受体有助于肿瘤组成或微环境的特征 跨不同的种族群体。趋化因子及其受体对于确定转移性至关重要 肿瘤细胞的目的地通过支持肿瘤血管生成和免疫细胞募集。趋化因子 受体CXCR4和ACKR3是趋化因子CXCL12的共受体，在BRCA转移中至关重要。 CXCR4在BRCA肿瘤和肿瘤脉管系统中的ACKR3中过表达。我们的初步数据指示 ACKR3和CXCR4在散装乳腺癌肿瘤组织的相反方向上的表达不同 不同的种族群体。我们还确定ACKR3和CXCR4在肿瘤子集中的表达不同 细胞，肿瘤内皮细胞。该项目的目的是阐明ACKR3和CXCR4的模式 在不同的肿瘤细胞子集中的表达以及这些受体如何促进肿瘤组成 以及来自不同种族群体的女性最终传播。我们提出了两个具体目标以实现 这个目标。 AIM 1：从不同种族的样品中确定BRCA中的ACKR3和CXCR4信号通路 组。识别控制ACKR3和CXCR4在BRCA中控制ACKR3和CXCR4的基因调节网络 不同的种族群体将表明这些受体对BRCA分布的贡献。目标2。确定CR 来自大致多样化的患者组织样品的乳腺肿瘤细胞亚群中的单细胞水平表达。清楚的 细胞种群功能将进行建模，并使用来自不同种族的BRCA人体组织进行定量分析 组，并通过测试增强ACKR3和CXCR4活性的因素是否可以反转 阻断受体微环境相互作用。这些发现将揭示细胞和分子 驱动ACKR3和CXCR4以改变BRCA分布中的肿瘤景观的贡献，包括肿瘤 脉管系统原位，有可能在转移性部位。知道这些分子特征将具有深远的角度 对热发育的影响，更好的临床试验发展并最终减轻癌症 差异。此外，这将使PI能够制定她的研究计划，收集初步数据以寻求 主流资金并允许她在旧金山提供和吸引种族多元化的学生人数 州立大学，包括43％的人数不足的学生，可以进行癌症生物学的激动人心的机会 研究并准备他们面对打击癌症差异的挑战。