Abstract 4613: Inhibition of myosin II in triple-negative breast cancer cells limits macrophage recruitment in a 3D environment

Abstract

Abstract Among all breast cancer subtypes, triple-negative breast cancer (TNBC) exhibits the least favorable outcomes with a complex tumor microenvironment that facilitates metastatic progression. Remodeling of the extracellular matrix at the tumor invasive front is associated with increased cancer cell motility and poor outcomes. Myosin II, a key cytoskeletal regulator, plays a central role in cancer cell metastatic potential. In the clinic, high expression of myosin II in breast tumors has been associated with distant metastasis and lower survival rates. Interestingly, breast tumors overexpressing myosin II exhibited a higher density of tumor-associated macrophages and an immunosuppressive microenvironment. However, the relationship between myosin II activation in TNBC cancer cells and macrophage recruitment 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. Using a panel of TNBC cell lines we found that high myosin II expression in cancer cells correlated with higher macrophage recruitment in a 3D matrix. Pharmacologic or genetic inhibition of myosin II reduced macrophage recruitment. Furthermore, using our microfluidic devices, we controlled the spatial distribution of cancer cells in a 3D matrix and separated the role of cancer cell-secreted paracrine factors from cancer cell-mediated matrix remodeling on macrophage recruitment. Analysis of matrix remodeling over time revealed that targeting myosin II in cancer cells limited the establishment of migratory tracks that facilitated macrophage recruitment. In sum, our studies revealed the critical role of cancer cell-driven matrix remodeling in promoting macrophage infiltration that can be therapeutically targeted to reverse the establishment of an immunosuppressive microenvironment. Citation Format: Youngbin Cho, Ruxuan Li, Ioannis Zervantonakis. Inhibition of myosin II in triple-negative breast cancer cells limits macrophage recruitment in a 3D environment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4613.