1. Apoptotic tumor cell-derived microRNA-375 uses CD36 to alter the tumor-associated macrophage phenotype.
- Author
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Frank AC, Ebersberger S, Fink AF, Lampe S, Weigert A, Schmid T, Ebersberger I, Syed SN, and Brüne B
- Subjects
- Animals, Apoptosis, Breast Neoplasms immunology, Breast Neoplasms pathology, CD36 Antigens immunology, Cell Movement, Chemokine CCL2 genetics, Chemokine CCL2 immunology, Coculture Techniques, Female, Gene Expression Profiling, Humans, MCF-7 Cells, Macrophages pathology, Mice, Mice, Nude, MicroRNAs immunology, Paxillin genetics, Paxillin immunology, Phenotype, Signal Transduction, Spheroids, Cellular immunology, Spheroids, Cellular pathology, Tensins genetics, Tensins immunology, Tumor Burden, Tumor Microenvironment genetics, Tumor Microenvironment immunology, Xenograft Model Antitumor Assays, Breast Neoplasms genetics, CD36 Antigens genetics, Gene Expression Regulation, Neoplastic, Macrophages immunology, MicroRNAs genetics
- Abstract
Tumor-immune cell interactions shape the immune cell phenotype, with microRNAs (miRs) being crucial components of this crosstalk. How they are transferred and how they affect their target landscape, especially in tumor-associated macrophages (TAMs), is largely unknown. Here we report that breast cancer cells have a high constitutive expression of miR-375, which is released as a non-exosome entity during apoptosis. Deep sequencing of the miRome pointed to enhanced accumulation of miR-375 in TAMs, facilitated by the uptake of tumor-derived miR-375 via CD36. In macrophages, miR-375 directly targets TNS3 and PXN to enhance macrophage migration and infiltration into tumor spheroids and in tumors of a xenograft mouse model. In tumor cells, miR-375 regulates CCL2 expression to increase recruitment of macrophages. Our study provides evidence for miR transfer from tumor cells to TAMs and identifies miR-375 as a crucial regulator of phagocyte infiltration and the subsequent development of a tumor-promoting microenvironment.
- Published
- 2019
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