Metastatic progression of cancer is a complex and clinically daunting process1,2,3,4. We previously identified a set of human microRNAs (miRNAs) that robustly suppress breast cancer metastasis to lung and bone5,6 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 cancers7,8, 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.
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We thank the members of the Tavazoie laboratory, Saeed Tavazoie, M. Tavazoie, S. Kurdistani, C. Alarcon and E. Mandel for comments on previous versions of this manuscript. We thank V. Gueorguiev and the Memorial Sloan-Kettering Cancer Center’s Molecular Cytology Core Facility for help. We thank the Memorial Sloan-Kettering Cancer Center’s High-Throughput Screening Core Facility for providing the shRNAs. We thank H. Lee for cloning assistance. K.J.P. is an A*STAR National Science Scholar. S.F.T. is a Department of Defense Era of Hope Scholar and the Leon Hess Head of the Elizabeth and Vincent Mayer Laboratory at Rockefeller University.
This file contains Supplementary Figures 1-24 with legends, Supplementary Tables 1-9, a Supplementary Discussion and additional references.