Abstract
Simple SummaryThe 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.
Highlights
Despite diagnostic and therapeutic advances, breast cancer (BC) remains the most prevalent cancer worldwide and continues to account for a substantial number of tumorassociated deaths [1]
The progression of and prognosis for BC and other tumor entities is largely determined by the tumor microenvironment (TME) [2,3,4]
Tumor-derived miRs are detectable in the serum of cancer patients and even serve as diagnostic biomarkers [15,16], since different tumor entities are characterized by specific miR expression profiles [17]
Summary
Despite diagnostic and therapeutic advances, breast cancer (BC) remains the most prevalent cancer worldwide and continues to account for a substantial number of tumorassociated deaths [1]. The progression of and prognosis for BC and other tumor entities is largely determined by the tumor microenvironment (TME) (i.e., by stromal cells including various immune cells and fibroblasts) [2,3,4]. Amongst the tumor-infiltrating immune cells, tumor-associated macrophages (TAM), predominantly derived from blood monocytes, play a crucial role. Tumor cells were shown to affect surrounding stromal cells by releasing microRNAs (miRs) [13,14]. Along these lines, tumor-derived miRs are detectable in the serum of cancer patients and even serve as diagnostic biomarkers [15,16], since different tumor entities are characterized by specific miR expression profiles [17]. The effects of miRs often depend on already established or alternatively induced gene expression programs
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