Identifying feedback loop mechanisms between neutrophils and macrophages that cause sustained, pro-metastatic inflammation

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Over half of breast cancer-related deaths are due to the recurrence of metastatic breast cancer five or more years after initial diagnosis and treatment [1]. Metastasis requires four key steps: 1) tumor cells leave the primary tumor; 2) tumor cells enter new tissue; 3) disseminated tumor cells (DTCs) re-initiate proliferation; and 4) an inflammatory, metastasis-supporting microenvironment is established. Steps 1-2 are rarely amenable to intervention, as they usually occur before the primary tumor is detected. However, targeting steps 3-4 may ultimately reduce metastasis and its associated mortality.To accomplish this long-term goal, we must first determine how the metastasis-supporting, inflammatory microenvironment is established. Inflammation is commonly mediated by neutrophils—essential cells of the innate immune system. In response to infection and inflammation, neutrophils release neutrophil extracellular traps (NETs)—meshes of genomic DNA with ~40 associated proteins—into the extracellular space to trap harmful microorganisms. However, NETs can also facilitate metastasis after a period of tumor dormancy. Dr. Mikala Egeblad’s lab recently discovered that sustained lung inflammation drives quiescent DTCs to re-initiate proliferation in mice (step 3) and that NETs are essential to this process. My new preliminary data show that NET-associated proteins, e.g. high mobility group box 1 (HMGB1), can activate macrophages to secrete inflammasome-dependent interleukin (IL)-1ß, which in turn induces more NETs. I therefore hypothesize that a NET-macrophage feedback loop drives step 4 of the metastatic process. In aim 1, I will identify how macrophages sense NETs to induce IL-1ß secretion in vitro and in vivo, setting the stage for future experiments targeting this pathway. In aim 2, I will test the effects of NET-induced IL-1ß on the establishment of metastasis from quiescent DTCs. Three different IL-1ß blocking therapies are already approved for rheumatoid arthritis, so if NET-induced IL-1ß promotes metastasis from quiescent DTCs in the proposed models, these drugs could be tested in cancer therapy.