title: Melanoma miRNA trafficking controls tumour primary niche formation.
abstract: Melanoma originates in the epidermis and becomes metastatic after invasion into the dermis. Prior interactions between melanoma cells and dermis are poorly studied. Here, we show that melanoma cells directly affect the formation of the dermal tumour niche by microRNA trafficking before invasion. Melanocytes, cells of melanoma origin, are specialized in releasing pigment vesicles, termed melanosomes. In melanoma in situ, we found melanosome markers in distal fibroblasts before melanoma invasion. The melanosomes carry microRNAs into primary fibroblasts triggering changes, including increased proliferation, migration and pro-inflammatory gene expression, all known features of cancer-associated fibroblasts (CAFs). Specifically, melanosomal microRNA-211 directly targets IGF2R and leads to MAPK signalling activation, which reciprocally encourages melanoma growth. Melanosome release inhibitor prevented CAF formation. Since the first interaction of melanoma cells with blood vessels occurs in the dermis, our data suggest an opportunity to block melanoma invasion by preventing the formation of the dermal tumour niche.
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Shani
authors.initials: S
authors.lastname: Dror
authors.affiliation: Functional Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg 69120, Germany.
authors.forename: Laureen
authors.initials: L
authors.lastname: Sander
authors.affiliation: Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Hila
authors.initials: H
authors.lastname: Schwartz
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Danna
authors.initials: D
authors.lastname: Sheinboim
authors.affiliation: Institute of Pathology, Sheba Medical Center, Tel Hashomer 52621, Israel.
authors.forename: Aviv
authors.initials: A
authors.lastname: Barzilai
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Dishon
authors.affiliation: Department of Immunology, Institut Gustave Roussy, Université Paris, 94805 Villejuif, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Apcher
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Golan
authors.affiliation: Institute of Pathology, Sheba Medical Center, Tel Hashomer 52621, Israel.
authors.forename: Shoshana
authors.initials: S
authors.lastname: Greenberger
authors.affiliation: Institute of Pathology, Sheba Medical Center, Tel Hashomer 52621, Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Barshack
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Hagar
authors.initials: H
authors.lastname: Malcov
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Alona
authors.initials: A
authors.lastname: Zilberberg
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Lotan
authors.initials: L
authors.lastname: Levin
authors.affiliation: Imaging and Cytometry Core Facility, Unit for Electron Microscopy, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg 69120, Germany.
authors.forename: Michelle
authors.initials: M
authors.lastname: Nessling
authors.affiliation: The Bio-Imaging Unit, Hebrew University, Jerusalem 91904, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Friedmann
authors.affiliation: Cutaneous Biology Research Center, Department of Dermatology and MGH Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Vivien
authors.initials: V
authors.lastname: Igras
authors.affiliation: Coller School of Management, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ohad
authors.initials: O
authors.lastname: Barzilay
authors.affiliation: Institute of Pathology, E. Wolfson Medical Center, Holon 58100, Israel.
authors.forename: Hananya
authors.initials: H
authors.lastname: Vaknine
authors.affiliation: Institute of Pathology, E. Wolfson Medical Center, Holon 58100, Israel.
authors.forename: Ronen
authors.initials: R
authors.lastname: Brenner
authors.affiliation: Department of Chemical Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Assaf
authors.initials: A
authors.lastname: Zinger
authors.affiliation: Department of Chemical Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Avi
authors.initials: A
authors.lastname: Schroeder
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Pinchas
authors.initials: P
authors.lastname: Gonen
authors.affiliation: INSERM 1186, Gustave Roussy, Université Paris-Saclay, Villejuif 94805, France.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Khaled
authors.affiliation: Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Neta
authors.initials: N
authors.lastname: Erez
authors.affiliation: Functional Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg 69120, Germany.
authors.forename: Jörg D
authors.initials: JD
authors.lastname: Hoheisel
authors.affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Carmit
authors.initials: C
authors.lastname: Levy
mesh_terms: D000818:Animals; D001692:Biological Transport; D002465:Cell Movement / Q000235:genetics*; D004817:Epidermis / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D020460:Melanosomes / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: C549405:MIRN211 microRNA, human; D035683:MicroRNAs; C577982:Mirn211 microRNA, mouse