Abstract 130: Matrix remodeling promotes macrophage recruitment in breast cancer

Abstract A high number of tumor-associated macrophages (TAM) in breast tumors is associated with poor patient outcomes. Furthermore, activation of myosin II, a key cytoskeletal regulator, has been identified as a predictor of distant metastasis in triple negative breast cancer (TNBC). However, the relationship between myosin II activation in TNBC cancer cells and macrophage motility remains poorly understood. Here we employed a novel 3D microfluidic model of tumor-macrophage co-culture to study macrophage infiltration toward cancer cells with high spatiotemporal resolution and evaluation of extracellular matrix remodeling. Using a panel of TNBC cell lines we found that cancer cells with higher macrophage recruitment potential in a 3D matrix exhibited higher levels of myosin II activity. We found that macrophage infiltration was higher in decellurized extracellular matrices seeded with the high-macrophage recruiting cancer cell line EMT6 compared to the low-macrophage recruiting cancer cells E0771. Functional contractility analysis using traction microscopy revealed that EMT6 exerted higher matrix displacements compared to E0771 that could be suppressed by pharmacologically blocking myosin II in cancer cells or genetic silencing of the myosin regulatory light polypeptide 9. Consistent with these suppressive effects of targeting actomyosin contractility on matrix remodeling we also found that macrophage recruitment was reduced. These studies reveal the critical role of cancer cell-driven matrix remodeling in promoting macrophage infiltration that can be therapeutically targeted to revere the establishment of a macrophage-rich pro-tumorigenic tumor microenvironment. Citation Format: Ioannis K. Zervantonakis, Youngbin Cho. Matrix remodeling promotes macrophage recruitment in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 130.