Neutrophils drive vascular occlusion, tumour necrosis and metastasis

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 (July 2025) Neutrophils drive vascular occlusion, tumour necrosis and metastasis. Nature. ISSN 0028-0836 (Public Dataset)

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Abstract

Tumour necrosis is associated with poor prognosis in cancer1,2 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 Ly6GHighLy6CLow neutrophil population that was unable to extravasate in response to inflammatory challenges but formed neutrophil extracellular traps (NETs) more efficiently than classical Ly6GHighLy6CHigh 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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > cancer > metastasis organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neutrophils organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neutrophils organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neutrophils organs, tissues, organelles, cell types and functions
CSHL Authors:	Han, Xiao Sun, Lijuan Sivetz, Nicole He, Xueyan Egeblad, Mikala Adrover, Jose M. Fujii, Takeo DaBler-Plenker, Juliane Evans, Clary
Communities:	CSHL labs > Beyaz lab CSHL labs > Egeblad lab CSHL labs > Meyer Lab CSHL labs > Van Aelst lab School of Biological Sciences > Publications
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	16 July 2025
Date Deposited:	17 Jul 2025 12:51
Last Modified:	18 Jul 2025 16:07
Related URLs:	Publisher
Dataset ID:	GEO: GSE228588 GEO: GSE229953 GEO: GSE199515 GEO: GSE230098 GEO: GSE272502 GEO: GSE123366
URI:	https://repository.cshl.edu/id/eprint/41909

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