Paracrine CSF1 signaling regulates macrophage migration dynamics towards ovarian cancer cells in a 3D microfluidic model that recapitulates in vivo infiltration patterns in patient-derived xenograft models

Abstract

Ovarian cancer is the second most deadly gynecologic cancer in the United States, and tumorassociated macrophages in the ovarian cancer microenvironment are the most abundant immune cell type and are associated poor survival. Here, we utilize three-dimensional microfluidic assays to investigate the dynamics of macrophage infiltration towards ovarian cancer cells. Experimental results demonstrate that both ovarian cancer cell lines and patient-derived xenograft models promote the infiltration of macrophages into a 3D collagen type I extracellular matrix. Additionally, blocking CSF1 signaling reduced the number of recruited macrophages as well as migration speed, while macrophage recruitment was enhanced by addition of recombinant CSF1. We further demonstrated that results obtained with our microfluidic model are consistent with the recruitment of macrophages in vivo by patient-derived xenograft models, and that a xenograft model with high CSF1 expression showed an enhanced ability to recruit macrophages both in vitro and in vivo. These results highlight the role of CSF1 signaling in ovarian cancer, as well as the utility of microfluidic models in recapitulating the 3D ovarian cancer microenvironment.