Final Report Summary - BMDCMET (Innate and adaptive immune cell contribution to the pre-metastatic niche)
Bone marrow-derived cells (BMDCs) play a critical role in breast cancer metastasis. These cells influence each step of the metastatic cascade from intravasation into the blood stream to outgrowth of metastatic lesions. In addition, BMDCs may also prime future metastatic sites for incoming tumor cells and establish a ‘pre-metastatic niche.’ The aim of this proposal was to determine whether a pre-metastatic niche exists in the K14cre;EcadF/F;p53F/F mouse model of invasive lobular breast cancer and identify the BMDC population that is most important in this process. To address this goal, we proposed to 1) Perform an in depth kinetic characterization of disseminated tumor cell colonization of distant metastatic organs; and 2) Determine which BMDC population regulates the pre-metastatic niche and their functional significance to metastasis formation. For these studies, we utilized both K14cre;EcadF/F;p53F/F mice and a new metastasis model, developed by the Host lab. This metastasis model is based on the transplantation of K14cre;EcdF/F;p53F/F tumor pieces into the mammary glands of wild-type recipient mice, and subsequent surgical removal of the primary tumor. Metastasis occurs spontaneously and mice succumb to widespread, overt metastatic disease in lymph nodes, lungs, and gastrointestinal tract. Using this model, we found that metastasis occurs at the early stages of tumor progression, when tumors are relatively small in size. At the same time, factors released by the tumor also cause profound changes in the cellular composition of distant organs. Most notably, we observed a marked and significant expansion of neutrophils in the circulation, as well as an increased accumulation of these cells in future metastatic organs. Depletion of these neutrophils inhibited pulmonary metastasis formation dramatically, indicating that neutrophils support spreading of tumor cells to other organs. Interestingly, mice treated with neutrophil-depleting antibodies in the neoadjuvant setting displayed a profound reduction in pulmonary metastasis, whereas metastases in the adjuvant group were equivalent to controls. These data indicate that neutrophils play a prominent role during the very early stages of the metastatic cascade. Our preliminary data suggest that these tumor-educated neutrophils can suppress the activation of T cells, as one mechanism by which they may promote metastasis. Current efforts are underway to determine how mammary tumors regulate the function and recruitment of neutrophils. This grant has allowed us to establish a crucial role for neutrophils in breast cancer metastasis.