Neutrophils drive vascular occlusion, tumour necrosis and metastasis

• 成果类型: Article
• 署名作者: Adrover, Jose M.; Han, Xiao; Sun, Lijuan; Fujii, Takeo; Sivetz, Nicole; Dassler-Plenker, Juliane; Evans, Clary; Peters, Jessica; He, Xue-Yan; Cannon, Courtney D.; Ho, Won Jin; Raptis, George; Powers, R. Scott; Egeblad, Mikala
• 署名单位: Cold Spring Harbor Laboratory; Johns Hopkins University; Johns Hopkins Medicine; Francis Crick Institute; State University of New York (SUNY) System; Stony Brook University; Northwell Health; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Northwell Health; Johns Hopkins University; Johns Hopkins Medicine; Washington University (WUSTL); Rutgers University System; Rutgers University New Brunswick; Rutgers University Biomedical & Health Sciences; Rutgers Cancer Institute of New Jersey
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09278-3
• 发表日期: 2025-09-01
• 页码: 484-+
• 关键词: extracellular dna traps; mesenchymal transition; hematopoietic stem; breast-cancer; murine models; l-selectin; cells; inhibition; disease; RISK

摘要

Tumour necrosis is associated with poor prognosis in cancer(1,2) and is thought to occur passively when tumour growth outpaces nutrient supply. Here we report, however, that neutrophils actively induce tumour necrosis. In multiple cancer mouse models, we found a tumour-elicited Ly6G(High)Ly6C(Low) neutrophil population that was unable to extravasate in response to inflammatory challenges but formed neutrophil extracellular traps (NETs) more efficiently than classical Ly6G(High)Ly6C(High) neutrophils. The presence of these 'vascular-restricted' neutrophils correlated with the appearance of a 'pleomorphic' necrotic architecture in mice. In tumours with pleomorphic necrosis, we found intravascular aggregates of neutrophils and NETs that caused occlusion of the tumour vasculature, driving hypoxia and necrosis of downstream vascular beds. Furthermore, we found that cancer cells adjacent to these necrotic regions (that is, in 'perinecrotic' areas) underwent epithelial-to-mesenchymal transition, explaining the paradoxical metastasis-enhancing effect of tumour necrosis. Blocking NET formation genetically or pharmacologically reduced the extent of tumour necrosis and lung metastasis. Thus, by showing that NETs drive vascular occlusion, pleomorphic necrosis and metastasis, we demonstrate that tumour necrosis is not necessarily a passive byproduct of tumour growth and that it can be blocked to reduce metastatic spread.