Abstract SY38-01: Inflammation-induced neutrophil extracellular traps (NETs) awaken dormant cancer in the lung microenvironment

Abstract

Abstract To elucidate mechanisms of cancer metastasis and recurrence from minimal residual disease, we use intravital imaging allowing for long-term visualization of cancer cells and surrounding host cells in living mice. Using intravital imaging, we found that neutrophils, the most abundant type of leukocytes in blood, form neutrophil extracellular traps (NETs) near disseminated cancer cells in the lung of mice during experimental inflammation. NETs are pathogen-trapping structures generated by expulsion of the neutrophil's DNA with associated proteolytic enzymes in response to, e.g., infections. However, we found that metastatic breast cancer cells themselves can induce neutrophils to form metastasis-supporting NETs, in the absence of infection. We also found NETs in clinical samples of metastatic, triple-negative human breast cancer. Using mouse models, we determined that NETs promote metastasis by facilitating proteolytic extracellular matrix remodeling. Pharmacologic inhibition of NET formation or digestion of NETs with DNase I-coated nanoparticles markedly reduced lung metastases in mice. Our data suggest that induction of NETs is an important host-mediated mechanism of promoting metastasis and a potential therapeutic target. Citation Format: Mikala Egeblad. Inflammation-induced neutrophil extracellular traps (NETs) awaken dormant cancer in the lung microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY38-01.