Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.
Institute of Molecular Biology gGmbH, Ackermannweg 4, 55128, Mainz, Germany.
Nat Commun. 2019 Mar 8;10(1):1135. doi: 10.1038/s41467-019-08989-2.
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.
肿瘤-免疫细胞相互作用塑造了免疫细胞表型，微小 RNA（miRs）是这种串扰的关键组成部分。它们如何传递以及如何影响其靶标景观，特别是在肿瘤相关巨噬细胞（TAMs）中，很大程度上是未知的。在这里，我们报告乳腺癌细胞具有高组成型表达 miR-375，它在细胞凋亡过程中作为非外泌体实体释放。miR 组学的深度测序表明，通过 CD36 摄取肿瘤衍生的 miR-375，促进了 miR-375 在 TAMs 中的积累。在巨噬细胞中，miR-375 直接靶向 TNS3 和 PXN 以增强巨噬细胞迁移并浸润肿瘤球体和异种移植小鼠模型中的肿瘤。在肿瘤细胞中，miR-375 调节 CCL2 的表达以增加巨噬细胞的募集。我们的研究为肿瘤细胞向 TAMs 转移 miR 提供了证据，并确定 miR-375 是吞噬细胞浸润和随后形成促进肿瘤微环境的关键调节剂。
