The Role of Endothelial ACKR1 in Triple-Negative Breast Cancer Metastasis
The Role of Endothelial ACKR1 in Triple-Negative Breast Cancer Metastasis
批准号:
10604865
负责人:
Samuel Roach
金额:
$5.27万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-05-16 至 2026-05-15
关键词:
AddressAdhesionsAffectAntibodiesBindingBiologicalBlood VesselsBlood capillariesBreast Cancer CellBreast Cancer PatientBreast Cancer TreatmentBreast cancer metastasisCXCL2 geneCell Adhesion MoleculesCellsCessation of lifeCirculationClinicalCoculture TechniquesControl AnimalCopying ProcessesDataDevelopmentDistantDistant MetastasisEndothelial CellsEndotheliumEpidermal Growth FactorErythrocytesEstrogen ReceptorsEvaluationExtravasationFatty acid glycerol estersGenesHumanImplantIntercellular JunctionsKnockout MiceLeukocytesLiteratureLocalized DiseaseLungMeasurementMediatingMembraneMetastatic Neoplasm to the LungMetastatic breast cancerMicrometastasisModalityMouse Cell LineMusNeoplasm Circulating CellsNeoplasm MetastasisOncologyPatientsPhysiciansPhysiologicalPrimary NeoplasmProcessProgesterone ReceptorsPrognostic MarkerResearchRoleScientistSiteStromal CellsStructure of parenchyma of lungSurvival RateSystemTailTestingTissuesTumor PromotionVeinscancer subtypescareercell typechemokinechemokine receptorcytokinediagnostic screeningeducation planningimprovedin vivoin vivo imaging systeminhibitorinsightmalignant breast neoplasmmammarymigrationmonolayermortalitymouse modelneoplastic cellneutralizing antibodyneutrophilnoveloverexpressionpreventprognostic indicatorshear stresstriple-negative invasive breast carcinomatumortumor growthtumor microenvironment
中文摘要
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
英文摘要
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.
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