title: Melanoma cell-derived exosomes promote epithelial-mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment.
abstract: The tumor microenvironment is abundant with exosomes that are secreted by the cancer cells themselves. Exosomes are nanosized, organelle-like membranous structures that are increasingly being recognized as major contributors in the progression of malignant neoplasms. A critical element in melanoma progression is its propensity to metastasize, but little is known about how melanoma cell-derived exosomes modulate the microenvironment to optimize conditions for tumor progression and metastasis. Here, we provide evidence that melanoma cell-derived exosomes promote phenotype switching in primary melanocytes through paracrine/autocrine signaling. We found that the mitogen-activated protein kinase (MAPK) signaling pathway was activated during the exosome-mediated epithelial-to-mesenchymal transition (EMT)-resembling process, which promotes metastasis. Let-7i, an miRNA modulator of EMT, was also involved in this process. We further defined two other miRNA modulators of EMT (miR-191 and let-7a) in serum exosomes for differentiating stage I melanoma patients from non-melanoma subjects. These results provide the first strong molecular evidence that melanoma cell-derived exosomes promote the EMT-resembling process in the tumor microenvironment. Thus, novel strategies targeting EMT and modulating the tumor microenvironment may emerge as important approaches for the treatment of metastatic melanoma.
authors.affiliation: The Hiram C. Polk, Jr., MD Department of Surgery, University of Louisville School of Medicine, Kosair Charities Clinical & Translational Research Building, 505 S. Hancock St, Room 407, Louisville, KY 40292, USA.
authors.forename: Deyi
authors.initials: D
authors.lastname: Xiao
authors.affiliation: The Hiram C. Polk, Jr., MD Department of Surgery, University of Louisville School of Medicine, Kosair Charities Clinical & Translational Research Building, 505 S. Hancock St, Room 407, Louisville, KY 40292, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Barry
authors.affiliation: The Hiram C. Polk, Jr., MD Department of Surgery, University of Louisville School of Medicine, Kosair Charities Clinical & Translational Research Building, 505 S. Hancock St, Room 407, Louisville, KY 40292, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kmetz
authors.affiliation: The Hiram C. Polk, Jr., MD Department of Surgery, University of Louisville School of Medicine, Kosair Charities Clinical & Translational Research Building, 505 S. Hancock St, Room 407, Louisville, KY 40292, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Egger
authors.affiliation: Biostatistics Shared Facility, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Pan
authors.affiliation: Biostatistics Shared Facility, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors.forename: Shesh N
authors.initials: SN
authors.lastname: Rai
authors.affiliation: The Hiram C. Polk, Jr., MD Department of Surgery, University of Louisville School of Medicine, Kosair Charities Clinical & Translational Research Building, 505 S. Hancock St, Room 407, Louisville, KY 40292, USA.
authors.forename: Jifu
authors.initials: J
authors.lastname: Qu
authors.affiliation: The Hiram C. Polk, Jr., MD Department of Surgery, University of Louisville School of Medicine, Kosair Charities Clinical & Translational Research Building, 505 S. Hancock St, Room 407, Louisville, KY 40292, USA. Electronic address: kelly.mcmasters@louisville.edu.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: McMasters
authors.affiliation: The Hiram C. Polk, Jr., MD Department of Surgery, University of Louisville School of Medicine, Kosair Charities Clinical & Translational Research Building, 505 S. Hancock St, Room 407, Louisville, KY 40292, USA. Electronic address: h0hao001@louisville.edu.
authors.forename: Hongying
authors.initials: H
authors.lastname: Hao
mesh_terms: D000328:Adult; D000368:Aged; D019898:Autocrine Communication; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000378:metabolism* / Q000473:pathology; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019899:Paracrine Communication; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D059016:Tumor Microenvironment
chemical_list: C546177:MIRN191 microRNA, human; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human; D020928:Mitogen-Activated Protein Kinases
keywords: Epithelial-to-mesenchymal transition; Exosomes; Melanoma; Microenvironment; Paracrine/autocrine; Tumor progression