Neutrophil extracellular traps formed during chemotherapy confer treatment resistance via TGF-β activation

Mousset, Alexandra, Lecorgne, Enora, Bourget, Isabelle, Lopez, Pascal, Jenovai, Kitti, Cherfils-Vicini, Julien, Dominici, Chloé, Rios, Géraldine, Girard-Riboulleau, Cédric, Liu, Bodu, Spector, David L, Ehmsen, Sidse, Renault, Shufang, Hego, Caroline, Mechta-Grigoriou, Fatima, Bidard, François-Clément, Terp, Mikkel Green, Egeblad, Mikala, Gaggioli, Cédric, Albrengues, Jean (April 2023) Neutrophil extracellular traps formed during chemotherapy confer treatment resistance via TGF-β activation. Cancer Cell, 41 (4). 757-775.e10. ISSN 1535-6108 (Public Dataset)

Abstract

Metastasis is the major cause of cancer death, and the development of therapy resistance is common. The tumor microenvironment can confer chemotherapy resistance (chemoresistance), but little is known about how specific host cells influence therapy outcome. We show that chemotherapy induces neutrophil recruitment and neutrophil extracellular trap (NET) formation, which reduces therapy response in mouse models of breast cancer lung metastasis. We reveal that chemotherapy-treated cancer cells secrete IL-1β, which in turn triggers NET formation. Two NET-associated proteins are required to induce chemoresistance: integrin-αvβ1, which traps latent TGF-β, and matrix metalloproteinase 9, which cleaves and activates the trapped latent TGF-β. TGF-β activation causes cancer cells to undergo epithelial-to-mesenchymal transition and correlates with chemoresistance. Our work demonstrates that NETs regulate the activities of neighboring cells by trapping and activating cytokines and suggests that chemoresistance in the metastatic setting can be reduced or prevented by targeting the IL-1β-NET-TGF-β axis.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > neoplasms organism description > animal diseases & disorders > cancer > cancer types > breast cancer 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 > drugs and therapies > chemotherapy diseases & disorders > inflammation organism description > animal > mammal organism description > animal > mammal > rodent > mouse 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 organism description > animal > mammal > rodent bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > TGF-beta diseases & disorders > viral diseases > coronavirus > therapies and treatments diseases & disorders > cancer > cancer types
CSHL Authors:	Liu, Bodu Spector, David L. Egeblad, Mikala
Communities:	CSHL labs > Egeblad lab CSHL labs > Spector lab CSHL Cancer Center Program CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL Cancer Center Program > Gene Regulation and Inheritance Program CSHL Cancer Center Shared Resources > Animal Services CSHL Cancer Center Shared Resources > Flow Cytometry Service CSHL Cancer Center Shared Resources > Histology Service CSHL Cancer Center Shared Resources > Microscopy Service
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	10 April 2023
Date Deposited:	20 Apr 2023 14:21
Last Modified:	09 Feb 2024 15:36
PMCID:	PMC10228050
Related URLs:	Publisher
Dataset ID:	GEO: GSE218119
URI:	https://repository.cshl.edu/id/eprint/40879

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