MicroRNA-200c Attenuates the Tumor-Infiltrating Capacity of Macrophages

Simple Summary The tumor microenvironment determines the prognosis and outcome for cancer patients. Herein, tumor-associated macrophages are not only highly abundant, but also play a crucial role in shaping a tumor-supporting microenvironment. Both their recruitment to the tumor as well as their functional polarization toward a pro-tumorigenic phenotype are mediated by tumor-derived factors including microRNAs. However, the impact of most microRNAs on the tumor cell-macrophage crosstalk remains to be elucidated. Thus, we reached out to investigate the role of hsa-miR-200c-3p (miR-200c) in tumor cell-macrophage interactions, as it was shown to be differentially expressed during cancer progression and metastasis. miR-200c was highly expressed in MCF7 breast tumor cells compared to macrophages. Furthermore, we identified a CD36-dependent uptake of miR-200c, derived from apoptotic tumor cells, into macrophages. In macrophages, elevated miR-200c levels reduced the expression of numerous migration-associated mRNAs, consequently reducing the capacity of macrophages to infiltrate into tumor spheroids. Finally, a distinct signature of miR-200c-repressed, predicted targets was identified, which strongly correlated with tumor infiltration. Targeting the miR-200c transfer from dying tumor cells to macrophages might therefore provide the opportunity to specifically modulate tumor-associated macrophage recruitment. Macrophages constitute a major part of the tumor-infiltrating immune cells. Within the tumor microenvironment, they acquire an alternatively activated, tumor-supporting phenotype. Factors released by tumor cells are crucial for the recruitment of tumor-associated macrophages. In the present project, we aimed to understand the role of hsa-miR-200c-3p (miR-200c) in the interplay between tumor cells and macrophages. To this end, we employed a coculture system of MCF7 breast tumor cells and primary human macrophages and observed the transfer of miR-200c from apoptotic tumor cells to macrophages, which required intact CD36 receptor in macrophages. We further comprehensively determined miR-200c targets in macrophages by mRNA-sequencing and identified numerous migration-associated mRNAs to be downregulated by miR-200c. Consequently, miR-200c attenuated macrophage infiltration into 3-dimensional tumor spheroids. miR-200c-mediated reduction in infiltration further correlated with a miR-200c migration signature comprised of the four miR-200c-repressed, predicted targets PPM1F, RAB11FIB2, RDX, and MSN.