The Role of Endothelial ACKR1 in Triple-Negative Breast Cancer Metastasis

内皮细胞 ACKR1 在三阴性乳腺癌转移中的作用

• 批准号: 10604865
• 负责人: Samuel Roach
• 金额: $ 5.27万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-16 至 2026-05-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604865
• 关键词: Address; Adhesions; Affect; Antibodies; Binding; Biological; Blood Vessels; Blood capillaries; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Breast cancer metastasis; CXCL2 gene; Cell Adhesion Molecules; Cells; Cessation of life; Circulation; Clinical; Coculture Techniques; Control Animal; Copying Processes; Data; Development; Distant; Distant Metastasis; Endothelial Cells; Endothelium; Epidermal Growth Factor; Erythrocytes; Estrogen Receptors; Evaluation; Extravasation; Fatty acid glycerol esters; Genes; Human; Implant; Intercellular Junctions; Knockout Mice; Leukocytes; Literature; Localized Disease; Lung; Measurement; Mediating; Membrane; Metastatic Neoplasm to the Lung; Metastatic breast cancer; Micrometastasis; Modality; Mouse Cell Line; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Oncology; Patients; Physicians; Physiological; Primary Neoplasm; Process; Progesterone Receptors; Prognostic Marker; Research; Role; Scientist; Site; Stromal Cells; Structure of parenchyma of lung; Survival Rate; System; Tail; Testing; Tissues; Tumor Promotion; Veins; cancer subtypes; career; cell type; chemokine; chemokine receptor; cytokine; diagnostic screening; education planning; improved; in vivo; in vivo imaging system; inhibitor; insight; malignant breast neoplasm; mammary; migration; monolayer; mortality; mouse model; neoplastic cell; neutralizing antibody; neutrophil; novel; overexpression; prevent; prognostic indicator; shear stress; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment

Metastasis is the most common cause of breast cancer mortality. Of the breast cancer subtypes, triple- negative breast cancer (TNBC) is the deadliest due to its increased likelihood to metastasize. Tumor cell extravasation is a critical step of metastasis and allows circulating tumor cells to exit the vasculature and seed distant tissues. Clear understanding of the major regulators of tumor cell extravasation will provide insights into the progression of TNBC metastasis. One potential regulator of TNBC cell extravasation is ACKR1. In many contexts, ACKR1 expression is required in endothelial cells (EC) for leukocyte extravasation. Endothelial ACKR1 binds CXCL2, a promigratory chemokine, and localizes it to EC junctions to guide neutrophils through leukocyte extravasation. CXCL2 expression in TNBC cells is also necessary for tumor cell extravasation from lung microvasculature and for tumor metastasis. Our preliminary data show that ACKR1 is required in at least one stromal cell type for TNBC metastasis from the primary tumor to the lung. These data suggest that endothelial ACKR1-CXCL2 interactions may mediate tumor cell extravasation in TNBC metastasis. Therefore, we hypothesize that endothelial ACKR1 promotes TNBC cell extravasation by retaining CXCL2 at EC junctions, resulting in the increased metastatic spread of TNBC. To address this hypothesis, we will examine the in vivo significance of endothelial ACKR1 expression using our validated ACKR1 endothelial cell-specific knockout mouse model. We will test the requirement for endothelial ACKR1 for metastasis of orthotopically implanted TNBC tumors to distant sites in the lung and for extravasation of circulating tumor cells into lung tissue. We will determine which steps of extravasation require ACKR1 by evaluating ACKR1-low and ACKR1-overexpressing ECs using an Ibidi flow co-culture system that recapitulates the shear stress conditions of pulmonary microvasculature. We will examine whether these steps are dependent on CXCL2 by introducing CXCL2-neutralizing antibodies to the Ibidi flow system and observing their effects on each extravasation step. Our proposed studies will establish the role of endothelial ACKR1 in TNBC metastatic progression and determine the specific steps of tumor cell extravasation in which endothelial ACKR1 and CXCL2 function. Understanding these processes may guide development of ACKR1 as a prognostic marker for metastasis and can provide mechanistic insight into candidate chemokine and chemokine receptor inhibitors under evaluation for treatment of breast cancer.

转移是乳腺癌死亡率的最常见原因。在乳腺癌亚型中，三重 阴性乳腺癌（TNBC）是最致命的，因为它的转移可能性增加。肿瘤细胞 渗出是转移的关键步骤，允许循环肿瘤细胞退出脉管系统和种子 遥远的组织。对肿瘤细胞渗出的主要调节剂的清晰了解将为您提供见解 TNBC转移的进展。 TNBC细胞渗出的一个潜在调节剂是ACKR1。在许多情况下，ACKR1表达是 在内皮细胞（EC）中需要进行白细胞渗出。内皮ACKR1绑定CXCL2，一种宣传 趋化因子，并将其定位到EC连接处，以引导中性粒细胞通过白细胞渗出。 CXCL2 TNBC细胞中的表达对于肿瘤细胞从肺微举行和肿瘤中也是必要的 转移。我们的初步数据表明，在TNBC至少一种基质细胞类型中需要ACKR1 从原发性肿瘤到肺的转移。这些数据表明内皮ACKR1-CXCL2相互作用 可以介导TNBC转移中的肿瘤细胞渗出。因此，我们假设内皮ACKR1 通过在EC连接处保留CXCL2来促进TNBC细胞的渗出，从而增加 TNBC的转移扩散。 为了解决这一假设，我们将检查内皮ACKR1表达的体内意义 使用我们经过验证的ACKR1内皮细胞特异性基因敲除鼠标模型。我们将测试要求 内皮ACKR1用于原位植入的TNBC肿瘤转移到肺部远处的位点 循环肿瘤细胞渗入肺组织。我们将确定哪些溢出步骤需要 通过使用IBIDI流共文化系统评估ACKR1 ACKR1-low和ACKR1过表达ECS 概括了肺微举行的剪切应力条件。我们将检查这些步骤是否 通过将CXCL2中和抗体引入IBIDI流量系统并观察，取决于CXCL2 它们对每个溢出步骤的影响。 我们提出的研究将确定内皮ACKR1在TNBC转移进展和 确定内皮ACKR1和CXCL2功能的肿瘤细胞渗出的特定步骤。 了解这些过程可能指导ACKR1作为转移和 可以在评估中提供有关候选趋化因子和趋化因子受体抑制剂的机械洞察力 用于治疗乳腺癌。