Tumor Tension Induces Persistent Inflammation and Promotes Breast Cancer Aggression

Abstract : Human breast tumors are highly fibrotic and their ECMs are stiffer relative to benign lesions. More recently, we established positive correlations between the number and location of infiltrating immune cells and ECM stiffness in human breast tumors. This has led us to hypothesize that TAMs drive tissue fibrosis and subsequently may stimulate inflammatory signaling. Using the MMTV-PyMT model, early macrophage not only ablated lung metastases, but demonstrated an anti-fibrotic role for macrophages as depicted by a decrease in fibrillar collagen and a reduction in ECM stiffness. Interestingly, we observed a striking loss of phospho-STAT3 and FAK signaling when mice were treated with a CSF1 antagonist. Furthermore, when mice were treated with a LOX inhibitor, phospho-STAT3 levels decreased in tumor cells. We also found that LOX inhibitor treatment caused a shift in the cytokine milieu consistent with an anti-tumor immune response. Moreover, tumor cells that lacked STAT3 manifest an analogous trend in cytokine milieu in vivo. Lastly, we demonstrated that ECM stiffness increased in phospho-STAT3 in tumor cells in vitro. Collectively, our data suggest macrophage infiltration promotes fibrosis that stimulates inflammatory signaling in tumor cells during early mammary tumorigenesis - and this feed-forward loop induces a pro-tumor immune response.