DVT-primed neutrophils reshape the brain microenvironment to promote brain metastasis
Brain metastasis (BrM) is a devastating complication of triple-negative breast cancer (TNBC), yet how host macroenvironmental conditions influence brain metastatic susceptibility remains poorly understood. Here, we investigated the impact of deep vein thrombosis (DVT), a common complication in patients with cancer, on TNBC brain metastasis. Analysis of a large clinical cohort identified DVT as an…
Deep vein thrombosis (DVT), a frequent complication of cancer, has been found to significantly increase the risk of brain metastasis (BrM) in triple-negative breast cancer (TNBC) patients. A large clinical study identified DVT as an independent risk factor for BrM in metastatic breast cancer patients. In two syngeneic TNBC models, DVT enhanced brain metastasis without altering primary tumor growth or lung metastasis.
The mechanism behind this effect involved DVT increasing neutrophil accumulation in the brain metastatic microenvironment. Depleting neutrophils eliminated the metastasis-promoting effect of DVT. Analysis of peripheral blood cells showed that DVT reprogrammed circulating neutrophils to adopt migratory and inflammatory profiles, characterized by neutrophil extracellular trap (NET) formation.
DVT increased the expression of CXCR2 on neutrophils and enhanced their recruitment to the brain. Additionally, DVT led to a significant rise in circulating NETs. Overall, these findings reveal DVT as a systemic driver of TNBC brain metastasis, establishing a link between cancer-associated thrombosis and brain metastatic susceptibility.
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