title: A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells.
abstract: Metastatic progression of cancer is a complex and clinically daunting process. We previously identified a set of human microRNAs (miRNAs) that robustly suppress breast cancer metastasis to lung and bone and which display expression levels that predict human metastasis. Although these findings revealed miRNAs as suppressors of cell-autonomous metastatic phenotypes, the roles of non-coding RNAs in non-cell-autonomous cancer progression processes remain unknown. Here we reveal that endogenous miR-126, an miRNA silenced in a variety of common human cancers, non-cell-autonomously regulates endothelial cell recruitment to metastatic breast cancer cells, in vitro and in vivo. It suppresses metastatic endothelial recruitment, metastatic angiogenesis and metastatic colonization through coordinate targeting of IGFBP2, PITPNC1 and MERTK--novel pro-angiogenic genes and biomarkers of human metastasis. Insulin-like growth factor binding protein 2 (IGFBP2) secreted by metastatic cells recruits endothelia by modulating IGF1-mediated activation of the IGF type-I receptor on endothelial cells; whereas c-Mer tyrosine kinase (MERTK) receptor cleaved from metastatic cells promotes endothelial recruitment by competitively antagonizing the binding of its ligand GAS6 to endothelial MERTK receptors. Co-injection of endothelial cells with breast cancer cells non-cell-autonomously rescues their miR-126-induced metastatic defect, revealing a novel and important role for endothelial interactions in metastatic initiation. Through loss-of-function and epistasis experiments, we delineate an miRNA regulatory network's individual components as novel and cell-extrinsic regulators of endothelial recruitment, angiogenesis and metastatic colonization. We also identify the IGFBP2/IGF1/IGF1R and GAS6/MERTK signalling pathways as regulators of cancer-mediated endothelial recruitment. Our work further reveals endothelial recruitment and endothelial interactions in the tumour microenvironment to be critical features of metastatic breast cancer.
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.
authors.forename: Kim J
authors.initials: KJ
authors.lastname: Png
authors.forename: Nils
authors.initials: N
authors.lastname: Halberg
authors.forename: Mitsukuni
authors.initials: M
authors.lastname: Yoshida
authors.forename: Sohail F
authors.initials: SF
authors.lastname: Tavazoie
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004730:Endothelium, Vascular / Q000473:pathology*; D004843:Epistasis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008113:Liver Neoplasms / Q000098:blood supply / Q000473:pathology / Q000556:secondary; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology / Q000556:secondary; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D018085:Regulon / Q000235:genetics*; D015398:Signal Transduction; D016019:Survival Analysis; D000076202:c-Mer Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D007334:Insulin-Like Growth Factor I; D036341:Intercellular Signaling Peptides and Proteins; D026901:Membrane Transport Proteins; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; D020794:Receptor Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D000076202:c-Mer Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C498779:IGF2BP2 protein, human; C527111:MIRN126 microRNA, human; C107847:PITPNC1 protein, human; C097072:MERTK protein, human