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.

转移是导致乳腺癌死亡的最常见原因。在乳腺癌亚型中，三倍