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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Cancer Cell |
| Vol/bind | 41 |
| Udgave nummer | 4 |
| Sider (fra-til) | 757-775.e10 |
| ISSN | 1535-6108 |
| DOI | |
| Status | Udgivet - 10. apr. 2023 |
Bibliografisk note
Funding Information:We thank the animal facility, histology core, flow cytometry core, and microscopy core (Molecular and Cellular Core Imaging, PICMI) at the Institute for Research on Cancer and Aging, Nice (IRCAN), and the 3D-Hub-S platform (supported by le Canceropôle PACA, la Région PACA, le Conseil Départemental 06, l’INSERM, l’ARC, and IBiSA) for technical support. The study was supported by the Canceropôle PACA (Emergence Grant to J.A. and Emergence Grant to P.L.), Association pour la Recherche sur le Cancer ( PDF20181208327 and PJA2021060003717 to J.A. and PJA20191209728 to C.G.), Institut National Du Cancer ( PLBIO21-073 to C.G., J.A., and F.M.-G. and PLBIO2018-138 to C.G.), French National Research Agency ( ANR-21-CE14-0006 to J.A., ANR-11-LABX-0028-01 to University of Côte d'Azur and ANR-15-IDEX-01 ), Fondation pour la Recherche Médicale ( DEQ20180339183 to C.G.), National Infrastructure France Génomique ( ANR-10-INBS-09-03 and ANR-10-INBS-09-02 to G.R. and C.G.R.), and National Cancer Institute ( 5P01CA013106 -Project 3 to D.L.S). We thank T. Pukrop (University Hospital Regensburg) for the 410.4 cells.
Funding Information:
We thank the animal facility, histology core, flow cytometry core, and microscopy core (Molecular and Cellular Core Imaging, PICMI) at the Institute for Research on Cancer and Aging, Nice (IRCAN), and the 3D-Hub-S platform (supported by le Canceropôle PACA, la Région PACA, le Conseil Départemental 06, l'INSERM, l'ARC, and IBiSA) for technical support. The study was supported by the Canceropôle PACA (Emergence Grant to J.A. and Emergence Grant to P.L.), Association pour la Recherche sur le Cancer (PDF20181208327 and PJA2021060003717 to J.A. and PJA20191209728 to C.G.), Institut National Du Cancer (PLBIO21-073 to C.G. J.A. and F.M.-G. and PLBIO2018-138 to C.G.), French National Research Agency (ANR-21-CE14-0006 to J.A. ANR-11-LABX-0028-01 to University of Côte d'Azur and ANR-15-IDEX-01), Fondation pour la Recherche Médicale (DEQ20180339183 to C.G.), National Infrastructure France Génomique (ANR-10-INBS-09-03 and ANR-10-INBS-09-02 to G.R. and C.G.R.), and National Cancer Institute (5P01CA013106-Project 3 to D.L.S). We thank T. Pukrop (University Hospital Regensburg) for the 410.4 cells. A.M. C.G. and J.A. designed and directed the project. A.M. and J.A. performed all experiments and analyzed data; I.B. K.J. C.D. P.L. and E.L. helped with experiments involving animals; I.B. generated the cell lines expressing mCherry and luciferase; J.C.-V. designed the flow cytometry panels and helped in their analysis; F.-C.B. F.M.-G. S.R. and C.H. helped analyze plasma NET levels in human samples; M.G.T. and S.E. helped analyze the presence of neutrophils and NETs in patients’ primary tumors; G.R. and C.G.-R helped analyze RNA-sequencing data; B.L. generated the PyMT cell line in the laboratory of D.L.S.; J.A. A.M. and E.L. wrote the manuscript. C.D. P.L. C.G. M.G.T. J.C.-V. and M.E. provided feedback on the manuscript. M.E. is a member of the research advisory board for brensocatib for Insmed, Inc. a member of the scientific advisory board for Vividion Therapeutics, Inc. and a consultant for Protalix, Inc. and holds shares in Agios Pharmaceuticals, Inc. J.A. C.G. and A.M. have a patent related to this work (EP22306004). We support inclusive, diverse, and equitable conduct of research.
Publisher Copyright:
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