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Abstract
Simple SummaryBrain metastasis is one of the common complications associated with breast cancers. Neutrophils form the predominant type of circulating white blood cells and play an important role in tumor pathogenesis. However, the role of neutrophils in the evolution of brain metastasis of breast cancers has not been clearly understood. Using simple neutrophil-tumor cell-culture models, we studied the possible biomolecular mechanisms by which the brain-metastatic breast cancer cells could potentially re-program the neutrophils as a tumor-promoting strategy, and how drug-induced inhibition of certain key neutrophil functionalities could help reverse this behavior. Brain metastasis is one of the main causes of mortality among breast cancer patients, but the origins and the mechanisms that drive this process remain poorly understood. Here, we report that the upregulation of certain CXCR2-associated ligands in the brain metastatic variants of the breast cancer cells (BrM) dynamically activate the corresponding CXCR2 receptors on the neutrophils, thereby resulting in the modulation of certain key functional neutrophil responses towards the BrM. Using established neutrophil-tumor biomimetic co-culture models, we show that the upregulation of CXCR2 increases the recruitment of Tumor-Associated Neutrophils (TANs) towards the BrM, to enable location-favored formation of Neutrophil Extracellular Traps (NETs). Inhibition of CXCR2 using small molecule antagonist AZD5069 reversed this behavior, limiting the neutrophil responses to the BrM and retarding the reciprocal tumor development. We further demonstrate that abrogation of NETs formation using Neutrophil Elastase Inhibitor (NEI) significantly decreases the influx of neutrophils towards BrM but not to their parental tumor, suggesting that CXCR2 activation could be used by the brain metastatic tumors as a mechanism to program the tumor-infiltrating TANs into a pro-NETotic state, so as to assume a unique spatial distribution that assists in the subsequent migration and invasion of the metastatic tumor cells. This new perspective indicates that CXCR2 is a critical target for suppressing neutrophilic inflammation in brain metastasis.
Highlights
The brain is considered to be one of the most common organs of hematogenous tumor metastasis, accounting for ~30% of all cancer metastases [1,2,3,4]
Neutrophil response to tumors is influenced by the autocrine and paracrine signaling within the Tumor-Immune Microenv (TIME), and different tumor types and subtypes possess inherently distinct cytokine expression profiles that could drive distinct neutrophil behavior [23,24,54]
The directional chemotaxis was quantified by counting the total number of cells that migrate over 24 h into the microfluidic reservoirs filled with the respective tumor conditioned media (TCM) (Schematically shown in Supplementary Figure S2A(i))
Summary
The brain is considered to be one of the most common organs of hematogenous tumor metastasis, accounting for ~30% of all cancer metastases [1,2,3,4]. Brain metastasis continues to remain the most intractable issue for patients suffering from metastatic breast cancers [9,10], with limited treatment options and poor survival (7~9 months). Whereas the choice of syst antitumor therapy relies heavily on receptor status studies conducted with biopsies o therapy relies heavily on receptor statusmetastases studies conducted biopsies of the metastatic metastatic lesions, brain biopsies with are not routinely performed due to the lesions, brain metastases biopsies are not routinely performed due to the morbidity of the bidity of the procedure, consequent to the availability of targeted agents and status o procedure, consequent to the availability of targeted agentsTherefore, and statusunderstanding of the extracranial extracranial disease at the time of diagnosis.
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