Preventing the Recurrence of Breast Cancer at the Metastatic Niche Using Resolution-Phase Macrophages

Breast cancer that recurs as metastatic disease many years after primary tumor resection and adjuvant therapy appears to arise from tumor cells that disseminated early in the course of the disease but did not develop into clinically apparent lesions. These long-term surviving, disseminated tumor cells maintain a state of dormancy and are resistant to conventional therapies that target actively dividing cells. The mechanisms responsible for maintaining the survival and outgrowth of dormant tumor cells remain largely unknown. Recently, we found that fibrotic-like microenvironment with extensive deposition of Type I collagen (Col-I) and fibroectin established at the site of the residing dormant tumor cells promoted the outbreak of residing dormant tumor cells. Therefore, we hypothesized that promoting resolution- the endogenous mechanism that terminates inflammation and fibrotic responses and actively directs tissue return to homeostasis- at the permissive site will `normalize` it and prevent metastatic outbreak. Here we demonstrate that soluble factors secreted by ex-vivo generated pro-resolving CD11b^low macrophages can inhibit the establishment of a fibrotic microenvironment by inhibiting TGFß1-induced differentiation of fibroblasts to myofibroblasts and consequently myofibroblasts expression of Col-I. Furthermore, these soluble factors prevented the metastatic outbreak of dormant tumor cells co-cultured with myofibroblasts in an in vitro 3D system that models tumor dormancy and metastatic outgrowth. Interestingly, our data also demonstrate that the blockade of fibroblast differentiation to myofibroblasts is not mediated by inhibition of the canonical signaling of TGFß1. Taken together our results demonstrate a pioneering conceptual approach to `normalize` the microenvironment that supports the outgrowth of disseminated dormant tumor cells by promoting the tissue resolution axis.