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Sci Rep. 2018 Aug 27;8(1):12905. doi: 10.1038/s41598-018-31323-7.

Metabolic reprogramming of stromal fibroblasts by melanoma exosome microRNA favours a pre-metastatic microenvironment.

Author information

1
Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
2
Department of Biomedical Engineering, Jacobs School of Medicine & Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA.
3
Flow and Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
4
Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
5
Department of Neurosurgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
6
Immune Analysis Facility, Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
7
South Campus Instrumentation Center, University at Buffalo, The State University of New York, Buffalo, NY, USA.
8
Genomics Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
9
New York Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY, USA.
10
Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
11
Department of Microbiology and Immunology, Jacobs School of Medicine & Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA.
12
Department of Pathology, Immunology and Otolaryngology, University of Pittsburgh School of Medicine and UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
13
Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. Marc.Ernstoff@RoswellPark.org.

Abstract

Local acidification of stroma is proposed to favour pre-metastatic niche formation but the mechanism of initiation is unclear. We investigated whether Human Melanoma-derived exosomes (HMEX) could reprogram human adult dermal fibroblasts (HADF) and cause extracellular acidification. HMEX were isolated from supernatants of six melanoma cell lines (3 BRAF V600E mutant cell lines and 3 BRAF wild-type cell lines) using ultracentrifugation or Size Exclusion Chromatography (SEC). Rapid uptake of exosomes by HADF was demonstrated following 18 hours co-incubation. Exposure of HDAF to HMEX leads to an increase in aerobic glycolysis and decrease in oxidative phosphorylation (OXPHOS) in HADF, consequently increasing extracellular acidification. Using a novel immuno-biochip, exosomal miR-155 and miR-210 were detected in HMEX. These miRNAs were present in HMEX from all six melanoma cell lines and were instrumental in promoting glycolysis and inhibiting OXPHOS in tumour cells. Inhibition of miR-155 and miR-210 activity by transfection of miRNA inhibitors into HMEX reversed the exosome-induced metabolic reprogramming of HADF. The data indicate that melanoma-derived exosomes modulate stromal cell metabolism and may contribute to the creation of a pre-metastatic niche that promotes the development of metastasis.

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