Exosome-mediated MIR211 modulates tumor microenvironment via the DUSP6-ERK5 axis and contributes to BRAFV600E inhibitor resistance in melanoma

The microRNA MIR211 is an important regulator of melanoma tumor cell behavior. Previous studies suggested that in certain tumors, MIR211 acted as a tumor suppressor while in others it behaved as an oncogenic regulator. When MIR211 is expressed in BRAFV600E-mutant A375 melanoma cells in mouse xenografts, it promotes aggressive tumor growth accompanied by increased cellular proliferation and angiogenesis. We demonstrate that MIR211 is transferred to adjacent cells in the tumor micro-environment via exosomes. Cross-species genome-wide transcriptomic analysis showed that human tumor-derived MIR211 interacts with the mouse transcriptome in the tumor microenvironment, and activates ERK5 signaling in human tumor cells via the modulation of a feedback loop. Human miR211 directly inhibits human DUSP6 protein phosphatase at the post-transcriptional level. We provide support for the hypothesis that DUSP6 inhibition conferred resistance of the human tumor cells to the BRAF inhibitor vemurafenib and to 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

Exosome-mediated MIR211 modulates tumor microenvironment via the DUSP6-ERK5 axis and contributes to BRAFV600E inhibitor resistance in melanoma

The microRNA MIR211 is an important regulator of melanoma tumor cell behavior. Previous studies suggested that in certain tumors, MIR211 acted as a tumor suppressor while in others it behaved as an oncogenic regulator. When MIR211 is expressed in BRAFV600E-mutant A375 melanoma cells in mouse xenografts, it promotes aggressive tumor growth accompanied by increased cellular proliferation and angiogenesis. We demonstrate that MIR211 is transferred to adjacent cells in the tumor micro-environment via exosomes. Cross-species genome-wide transcriptomic analysis showed that human tumor-derived MIR211 interacts with the mouse transcriptome in the tumor microenvironment, and activates ERK5 signaling in human tumor cells via the modulation of a feedback loop. Human miR211 directly inhibits human DUSP6 protein phosphatase at the post-transcriptional level. We provide support for the hypothesis that DUSP6 inhibition conferred resistance of the human tumor cells to the BRAF inhibitor vemurafenib and to 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

MicroRNA-211 modulates the DUSP6-ERK5 signaling axis to promote BRAF^(V600E)-driven melanoma growth in vivo and BRAF/MEK inhibitor resistance

Micro-RNAs are important post-transcriptional regulators of cell fate both in normal and disease states. miR-211 has previously been shown to be a direct regulator of metabolism in BRAF^(V600E)-mutant melanoma cells in vitro. Here we report that miR-211 expression promotes aggressive growth of BRAF^(V600E)-mutant melanoma xenografts in vivo. miR-211 promoted proliferation through post-transcriptional activation of ERK5 signaling, which has recently been implicated in BRAF and MEK inhibitor resistance. We therefore examined whether miR-211 similarly modulated melanoma resistance to the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. Consistent with this model, miR-211 expression increased melanoma cell resistance to both inhibitors and this resistance was associated with increased ERK5 phosphorylation. miR-211 mediates these effects by directly inhibiting the expression of DUSP6, an ERK5 pathway-specific phosphatase and now shown to be an miR-211 target gene. These results dissect the role of the miR-211-DUSP6-ERK5 axis in melanoma tumor growth and suggest a mechanism for the development of drug-resistant tumors and a target for overcoming resistance

MicroRNA-211 modulates the DUSP6-ERK5 signaling axis to promote BRAF^(V600E)-driven melanoma growth in vivo and BRAF/MEK inhibitor resistance

Micro-RNAs are important post-transcriptional regulators of cell fate both in normal and disease states. miR-211 has previously been shown to be a direct regulator of metabolism in BRAF^(V600E)-mutant melanoma cells in vitro. Here we report that miR-211 expression promotes aggressive growth of BRAF^(V600E)-mutant melanoma xenografts in vivo. miR-211 promoted proliferation through post-transcriptional activation of ERK5 signaling, which has recently been implicated in BRAF and MEK inhibitor resistance. We therefore examined whether miR-211 similarly modulated melanoma resistance to the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. Consistent with this model, miR-211 expression increased melanoma cell resistance to both inhibitors and this resistance was associated with increased ERK5 phosphorylation. miR-211 mediates these effects by directly inhibiting the expression of DUSP6, an ERK5 pathway-specific phosphatase and now shown to be an miR-211 target gene. These results dissect the role of the miR-211-DUSP6-ERK5 axis in melanoma tumor growth and suggest a mechanism for the development of drug-resistant tumors and a target for overcoming resistance