title: Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-dependent melanoma metastasis and angiogenesis.
abstract: Through in vivo selection of human cancer cell populations, we uncover a convergent and cooperative miRNA network that drives melanoma metastasis. We identify miR-1908, miR-199a-5p, and miR-199a-3p as endogenous promoters of metastatic invasion, angiogenesis, and colonization in melanoma. These miRNAs convergently target apolipoprotein E (ApoE) and the heat shock factor DNAJA4. Cancer-secreted ApoE suppresses invasion and metastatic endothelial recruitment (MER) by engaging melanoma cell LRP1 and endothelial cell LRP8 receptors, respectively, while DNAJA4 promotes ApoE expression. Expression levels of these miRNAs and ApoE correlate with human metastatic progression outcomes. Treatment of cells with locked nucleic acids (LNAs) targeting these miRNAs inhibits metastasis to multiple organs, and therapeutic delivery of these LNAs strongly suppresses melanoma metastasis. We thus identify miRNAs with dual cell-intrinsic/cell-extrinsic roles in cancer, reveal convergent cooperativity in a metastatic miRNA network, identify ApoE as an anti-angiogenic and metastasis-suppressive factor, and uncover multiple prognostic miRNAs with synergistic combinatorial therapeutic potential in melanoma.
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Nora
authors.initials: N
authors.lastname: Pencheva
authors.forename: Hien
authors.initials: H
authors.lastname: Tran
authors.forename: Colin
authors.initials: C
authors.lastname: Buss
authors.forename: Doowon
authors.initials: D
authors.lastname: Huh
authors.forename: Marija
authors.initials: M
authors.lastname: Drobnjak
authors.forename: Klaus
authors.initials: K
authors.lastname: Busam
authors.forename: Sohail F
authors.initials: SF
authors.lastname: Tavazoie
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009841:Oligonucleotides / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; C494646:DNAJA4 protein, human; D050956:HSP40 Heat-Shock Proteins; D026502:LDL-Receptor Related Proteins; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C577645:MIRN1908 microRNA, human; D035683:MicroRNAs; D009841:Oligonucleotides; C477371:locked nucleic acid; C098773:low density lipoprotein receptor-related protein 8; C531408:mirn199 microRNA, human