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:
Communities: CSHL Cancer Center 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
CSHL labs > Egeblad lab
CSHL labs > Spector lab
CSHL Cancer Center Program > Cancer Genetics and Genomics Program
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 10 April 2023
Date Deposited: 20 Apr 2023 14:21
Last Modified: 30 Apr 2024 17:59
PMCID: PMC10228050
Related URLs:
Dataset ID:
URI: https://repository.cshl.edu/id/eprint/40879

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