Stromal-driven and Amyloid β-dependent induction of neutrophil extracellular traps modulates tumor growth

Munir, Hafsa, Jones, James O, Janowitz, Tobias, Hoffmann, Markus, Euler, Maximilien, Martins, Carla P, Welsh, Sarah J, Shields, Jacqueline D (January 2021) Stromal-driven and Amyloid β-dependent induction of neutrophil extracellular traps modulates tumor growth. Nature Communications, 12 (1). p. 683. ISSN 2041-1723

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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.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > neoplasms organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell cycle > Neutrophil extracellular traps bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > amyloid-beta organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell cycle organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts organism description > animal > mammal diseases & disorders > cancer > cancer types > melanomas organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > prognosis bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organism description > animal > mammal > rodent
CSHL Authors:	Janowitz, Tobias
Communities:	CSHL labs > Janowitz lab CSHL Cancer Center Program CSHL Cancer Center Program > Cancer Genetics and Genomics Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	29 January 2021
Date Deposited:	28 Apr 2021 18:53
Last Modified:	13 Feb 2024 18:51
PMCID:	PMC7846803
URI:	https://repository.cshl.edu/id/eprint/39946

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