GSE125836
Exosome-mediated interaction in the tumor microenvironment modulates MIR211 response via the DUSP6-ERK5 axis and contributes to BRAFV600E inhibitor resistance in melanoma
It is uncertain whether the microRNA MIR211 is a tumor suppressor or an oncogene. To resolve this, we ectopically expressed MIR211 in BRAFV600E-mutant A375 melanoma cells and examined its effect in mouse xenografts. Ectopic MIR211 expression promoted aggressive tumor growth accompanied by increased cellular proliferation and angiogenesis. We provide evidence that MIR211 transfers to adjacent mouse endothelial cells via exosomes and alter the cellular properties.  Cross-species transcriptomic analysis showed that human tumor-derived MIR211 interacts with the mouse transcriptome and activates ERK5 signaling in tumor cells via modulation of a feedback loop. MIR211 directly inhibited the DUSP6 protein phosphatase, a novel MIR211 target, as confirmed by RNA immunopurification with RNA-seq and target cleavage assays. Finally, MIR211 expression conferred resistance to the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib, with associated increases in ERK5 phosphorylation. These findings are consistent with a model in which MIR211 regulates melanoma tumor proliferation and BRAF inhibitor resistance by inducing ERK5 signaling within the complex tumor microenvironment. We propose that the MIR211-ERK5 axis represents an important and sensitive regulatory arm in melanoma with potential theranostic applications. Overall design: A375, A375/211, and A375/211/PDK cells were injected into SCID mice and tumors were excised after 14 days. RNAs were isolated from tumors and sequenced. For Ago2 RIP-seq, A375 and A375/211 cells were subjected to immunopurification using an anti-Ago2 antibody and co-purified RNAs were sequenced.