DVT-primed neutrophils reshape the brain microenvironment to promote brain metastasis
- 1National Cancer Institute
Abstract
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 independent risk factor for BrM in patients with metastatic breast cancer. Using two syngeneic TNBC models, we demonstrated that DVT selectively enhanced brain metastasis without significantly affecting primary tumor growth or lung metastasis. Mechanistically, DVT increased neutrophil accumulation in the brain metastatic microenvironment, and neutrophil depletion completely abrogated the metastasis-promoting effect of DVT. Single-cell RNA sequencing of CD45+ cells in peripheral blood revealed that DVT reprogrammed circulating neutrophils toward migratory and inflammatory transcriptomic profiles characterized by neutrophil extracellular trap (NET) formation. DVT increased CXCR2 expression on circulating neutrophils and enhanced neutrophil recruitment in brain. Moreover, DVT significantly increased circulating NETs. Collectively, our findings identify DVT as a systemic driver of TNBC brain metastasis and reveal that DVT primes circulating neutrophils toward enhanced vascular recruitment and NET formation, providing a mechanistic link between cancer-associated thrombosis and brain metastatic susceptibility.
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BibTeX
@misc{endo2026dvtprimed,
title = {{DVT-primed neutrophils reshape the brain microenvironment to promote brain metastasis}},
author = {S. Endo and D. Rujchanarong and K. Keeran and K. Jeffries and W. Zhang and M. Bannister and K. Saeki and D. Wei and A. Tran and K. Ellison and A. Lee Fong and L. Lim and M. Kruhlak and R. Lake and C. A. Combs and P. Steeg and M. Kelly and S. Lipkowitz and Y. Kanthi and T. Fujii},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.15.751589},
url = {https://www.biorxiv.org/content/10.64898/2026.09.15.751589v1},
note = {CC0},
}
RIS
TY - UNPB
TI - DVT-primed neutrophils reshape the brain microenvironment to promote brain metastasis
AU - S. Endo
AU - D. Rujchanarong
AU - K. Keeran
AU - K. Jeffries
AU - W. Zhang
AU - M. Bannister
AU - K. Saeki
AU - D. Wei
AU - A. Tran
AU - K. Ellison
AU - A. Lee Fong
AU - L. Lim
AU - M. Kruhlak
AU - R. Lake
AU - C. A. Combs
AU - P. Steeg
AU - M. Kelly
AU - S. Lipkowitz
AU - Y. Kanthi
AU - T. Fujii
PY - 2026
DA - 2026/09/15
PB - bioRxiv
DO - 10.64898/2026.09.15.751589
UR - https://www.biorxiv.org/content/10.64898/2026.09.15.751589v1
AB - 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 independent risk factor for BrM in patients with metastatic breast cancer. Using two syngeneic TNBC models, we demonstrated that DVT selectively enhanced brain metastasis without significantly affecting primary tumor growth or lung metastasis. Mechanistically, DVT increased neutrophil accumulation in the brain metastatic microenvironment, and neutrophil depletion completely abrogated the metastasis-promoting effect of DVT. Single-cell RNA sequencing of CD45+ cells in peripheral blood revealed that DVT reprogrammed circulating neutrophils toward migratory and inflammatory transcriptomic profiles characterized by neutrophil extracellular trap (NET) formation. DVT increased CXCR2 expression on circulating neutrophils and enhanced neutrophil recruitment in brain. Moreover, DVT significantly increased circulating NETs. Collectively, our findings identify DVT as a systemic driver of TNBC brain metastasis and reveal that DVT primes circulating neutrophils toward enhanced vascular recruitment and NET formation, providing a mechanistic link between cancer-associated thrombosis and brain metastatic susceptibility.
ER -