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

Lee, Bongyong and Sahoo, Anupama and Sawada, Junko and Marchica, John and Sahoo, Sanjay and Layng, Fabiana I. A. L. and Finlay, Darren and Mazar, Joseph and Joshi, Piyush and Komatsu, Masanobu and Vuori, Kristiina and Powis, Garth and de Jong, Petrus R. and Ray, Animesh and Perera, Ranajan J. (2019) Exosome-mediated MIR211 modulates tumor microenvironment via the DUSP6-ERK5 axis and contributes to BRAFV600E inhibitor resistance in melanoma. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20190214-103134711

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Abstract

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.


Item Type:Report or Paper (Discussion Paper)
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https://doi.org/10.1101/548818DOIDiscussion Paper
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. bioRxiv preprint first posted online Feb. 13, 2019. Accession Number: All xenografts RNA-seq and Ago2 RIP-seq datasets have been deposited with Gene Expression Omnibus (GEO) under accession number GSE125836. We thank Sanford Burnham Prebys Medical Discovery Institute Analytical Genomics core, Bioinformatics core, Histology, and Microscope core and Metabolomics core for their support. We also thank Drs. Jeffrey M. Trent (Translational Genomics Institute, Phoenix, AZ) originally provided the 33 UACC cell lines and Neal Rosen (Memorial Sloan Kettering Cancer Center, New York, NY) provided the 5 SK-MEL and MeWo cell lines for the studies. This work was supported by National Institutes of Health grants [R21CA202197, CA165184, NCI 5P30CA030199 (SBP), P30 CA006973 (JHU SKCCC)] and Florida Department of Health, Bankhead-Coley Cancer Research Program [5BC08] to R.J.P. The authors declare that they have no competing interests.
Funders:
Funding AgencyGrant Number
NIHR21CA202197
NIHCA165184
NIH5P30CA030199
NIHP30 CA006973
Florida Department of HealthUNSPECIFIED
Record Number:CaltechAUTHORS:20190214-103134711
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190214-103134711
Official Citation:Exosome-mediated MIR211 modulates tumor microenvironment via the DUSP6-ERK5 axis and contributes to BRAFV600E inhibitor resistance in melanoma. Bongyong Lee, Anupama Sahoo, John Marchica, Junko Sawada, Sanjay Sahoo, Fabiana I. A. L. Layng, Darren Finlay, Joseph Mazar, Piyush Joshi, Masanobu Komatsu, Kristiina Vuori, Garth Powis, Petrus R. de Jong, Animesh Ray, Ranajan J. Perera. bioRxiv 548818; doi: https://doi.org/10.1101/548818
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:92932
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:14 Feb 2019 19:35
Last Modified:03 Oct 2019 20:49

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