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

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 beta, 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 beta -Secretase expression which correlates with poor prognosis. In summary, we report that CAFs drive NETosis to support cancer progression, identifying Amyloid beta as the protagonist and potential therapeutic target. The tumor microenvironment is composed of many cell types that crosstalk to modulate local immunity. Here the authors show that Amyloid beta proteins from cancer-associated fibroblasts (CAF) induce neutrophil extracellular trap (NET) production by neutrophils, while NET feeds back to activate CAF, thereby implicating Amyloid beta as a potential therapy target.

Automated summary

The study reveals that cancer-associated fibroblasts (CAF) induce the formation of neutrophil extracellular traps (NET) within tumors and systemically in the blood and bone marrow. These tumor-induced NETs are driven by a ROS-mediated pathway dependent on CAF-derived Amyloid beta peptide. Inhibition of NETosis skews neutrophils to an anti-tumor phenotype, while t-NETs enhance CAF activation.