Abstract
Tumors consist of cancer cells and a network of non-cancerous stroma. Cancer-associated fibroblasts (CAF) are known to support tumorigenesis, and are emerging as immune modulators. Neutrophils release histone-bound nuclear DNA and cytotoxic granules as extracellular traps (NET). Here we show that CAFs induce NET formation within the tumor and systemically in the blood and bone marrow. These tumor-induced NETs (t-NETs) are driven by a ROS-mediated pathway dependent on CAF-derived Amyloid β, a peptide implicated in both neurodegenerative and inflammatory disorders. Inhibition of NETosis in murine tumors skews neutrophils to an anti-tumor phenotype, preventing tumor growth; reciprocally, t-NETs enhance CAF activation. Mirroring observations in mice, CAFs are detected juxtaposed to NETs in human melanoma and pancreatic adenocarcinoma, and show elevated amyloid and β-Secretase expression which correlates with poor prognosis. In summary, we report that CAFs drive NETosis to support cancer progression, identifying Amyloid β as the protagonist and potential therapeutic target.
| Original language | English |
|---|---|
| Article number | 683 |
| Journal | Nature Communications |
| Volume | 12 |
| Issue number | 1 |
| ISSN | 1751-8628 |
| DOIs | |
| Publication status | Published - 01.12.2021 |
Funding
The authors would like to thank the staff at the ARES and CRUK Cambridge Institute animal facility for assistance with in vivo experiments, members of the CIMR flow cytometry core for assistance with flow cytometry applications, the Munos-Espin lab at the Hutchison/MRC Research Centre, the University of Cambridge for kindly providing the murine lung tumor sections, and Professor David Tuveson (Cold Spring Harbor Laboratories) for the murine pancreatic cancer cell line used in syngeneic models. This work was supported by the Medical Research Council Core funding. T.J. was supported by Cancer Research UK funding (C42738/ A24868), Cold Spring Harbor Laboratory (CSHL) and Northwell Health, the Pershing Square Foundation, and the US National Institute of Health for funding received as part of Cancer Center Support Development Funds granted to CSHL (5P30CA045508-31). M.H. was supported by the German Research Foundation (DFG) (CRC1181-C03) and S.J.W. was supported by a MRC Clinical Academic Research partnership grant (G101982).
Research Areas and Centers
- Academic Focus: Center for Infection and Inflammation Research (ZIEL)
- Centers: Center for Research on Inflammation of the Skin (CRIS)
DFG Research Classification Scheme
- 2.21-05 Immunology
