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

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

  • Cancer Cell. 2023 Apr 10;41(4):757-775.e10. doi: 10.1016/j.ccell.2023.03.008.
Alexandra Mousset 1,  Enora Lecorgne 2,  Isabelle Bourget 2,  Pascal Lopez 1,  Kitti Jenovai 1,  Julien Cherfils-Vicini 1,  Chloé Dominici 1,  Géraldine Rios 3,  Cédric Girard-Riboulleau 3,  Bodu Liu 4,  David L Spector 4,  Sidse Ehmsen 5,  Shufang Renault 6,  Caroline Hego 6,  Fatima Mechta-Grigoriou 7,  François-Clément Bidard 8,  Mikkel Green Terp 9,  Mikala Egeblad 4,  Cédric Gaggioli 10,  Jean Albrengues 11
Affiliations

Affiliations

  • 1 University Côte d'Azur, CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France.
  • 2 University Côte d'Azur, CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France; University Côte d'Azur, CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), 3D-Hub-S Facility, Nice, France.
  • 3 University Côte d'Azur, CNRS UMR7275, Institute of Molecular and Cellular Pharmacology (IPMC), Sophia Antipolis, France.
  • 4 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
  • 5 Department of Oncology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
  • 6 Circulating Tumor Biomarkers Laboratory, INSERM CIC-BT 1428, Department of Translational Research, Institut Curie, Paris, France.
  • 7 Stress and Cancer Laboratory, Institut Curie, INSERM, U830, PSL Research University, Ligue Nationale Contre le Cancer labeled Team, 26, Rue d'Ulm, 75005, Paris, France.
  • 8 Circulating Tumor Biomarkers Laboratory, INSERM CIC-BT 1428, Department of Translational Research, Institut Curie, Paris, France; Department of Medical Oncology, Institut Curie, Saint Cloud, Paris, France; University of Versailles Saint-Quentin-en-Yvelines (UVSQ), Paris-Saclay University, Saint Cloud, France.
  • 9 Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
  • 10 University Côte d'Azur, CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France; University Côte d'Azur, CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), 3D-Hub-S Facility, Nice, France. Electronic address: [email protected].
  • 11 University Côte d'Azur, CNRS UMR7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France. Electronic address: [email protected].
PMID: 37037615 DOI: 10.1016/j.ccell.2023.03.008
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.

Keywords

Breast Cancer; Lung Metastasis; TGFβ; chemoresistance; neutrophil extracellular traps.

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