Neutrophil extracellular traps as therapeutic targets in metastatic breast cancer

Cancer does not only affect the local site, but also the function of distant organs.

Although tumor-induced systemic effects account for the majority of cancer-related deaths, the underlying causes are still relatively unexplored.

We have identified tumor-induced neutrophil extracellular traps (NETs) as a novel mechanism by which a primary tumor can promote inflammation and impair functionality of peripheral vasculature and organs.

Building on this finding, the aim of the proposed research is to explore the role of NETs in breast cancer metastasis, with a special focus on the peripheral vasculature.

We will develop a novel targeting strategy for NETs and explore which tumor-derived factors that promote their formation. Specific aims of the project: Develop an AAV-mouse DNase I vector for long-term targeting of NETs. Investigate if the presence of intravascular NETs correlates to metastasis in breast cancer patients.

Analyse how global gene expression in peripheral vasculature (kidney, heart, liver, lung) is affected in mice with primary cancer at a distant site and which role NETs play in such changes.

Determine if tumor-induced intravascular NET formation predisposes for breast cancer metastasis due to alterations in the endothelial barrier function and if metastasis can be suppressed by inhibition of NETs.

Identify which tumor-derived circulating factors that promote NET formation to better predict which patients are at risk of developing intravascular NETs.