Stromal Amyloid β drives Neutrophil extracellular trap formation to augment tumour growth

Munir, Hafsa, Jones, James O, Janowitz, Tobias, Martins, Carla P, Welsh, Sarah J, Shields, Jacqueline D (January 2020) Stromal Amyloid β drives Neutrophil extracellular trap formation to augment tumour growth. BioRxiv. (Unpublished)

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Abstract

Tumors are comprised of cancer cells and a network of non-cancerous stromal cells. Cancer-associated fibroblasts (CAFs) are well known to support tumorigenesis and are emerging as immune modulators. While many leukocyte populations are well studied in cancer, neutrophils have received less attention. Neutrophils can release histone-bound nuclear DNA and cytotoxic granules as extracellular traps (NETs) in a process termed NETosis. Here, we show that CAFs induce formation of NETs both within the tumor microenvironment and at systemic levels in the blood and bone marrow. These tumor-induced NETs (t-NETs) are driven by a ROS-mediated pathway dependent on PAD4 and CD11b. Remarkably, CAF-derived Amyloid β was identified as the key factor driving t-NETosis, a protein with significance in both neurodegenerative and inflammatory disorders. Therapeutic inhibition of NETs in established tumors prevented growth, skewing neutrophils to a pro-inflammatory phenotype. Reciprocally, t-NETs enhanced CAF activation phenotypes. Mirroring murine observations, NETs were detected juxtaposed to CAFs in human melanoma and pancreatic adenocarcinoma, and elevated expression of amyloid and β-Secretase correlated with poor prognosis. In summary, we report the existence of cross-talk between CAFs and neutrophils within the tumour microenvironment whereby CAF-induced t-NETosis supports cancer progression, identifying Amyloid β as the protagonist and potential therapeutic target. Significance This study defines the existence of a pro-tumor immunomodulatory function of the stroma showing the induction of Neutrophil Extracellular Traps through CAF-derived Amyloid β. We term this novel process “Tumor-induced NETosis” (t-NETosis) and propose that therapeutic inhibition of this mechanism, which we observe in human melanoma and pancreatic cancer, has the potential to improve patient outcome.

Item Type:	Paper
Subjects:	diseases & disorders > cancer > cancer types > melanomas diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > drugs and therapies > tumor microenvironment
CSHL Authors:	Janowitz, Tobias
Communities:	CSHL labs > Janowitz lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	11 January 2020
Date Deposited:	13 Jul 2021 19:31
Last Modified:	29 Apr 2024 15:37
URI:	https://repository.cshl.edu/id/eprint/40283

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