A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells

Abstract

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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Figure 1: Endogenous miR-126 suppresses metastatic colonization.
Figure 2: Endogenous miR-126 non-cell-autonomously suppresses endothelial recruitment by breast cancer cells.
Figure 3: IGFBP2, PITPNC1 and MERTK promote metastatic colonization and angiogenesis.
Figure 4: IGFBP2 and MERTK mediate endothelial recruitment through IGF1/IGF1R and GAS6/MERTK pathways respectively.

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Gene Expression Omnibus

Data deposits

The data from miR-126-overexpressing and MDA/LM2 microarrays are deposited in Gene Expression Omnibus under accession numbers GSE23905 and GSE23904 respectively.

References

  1. 1

    Chiang, A. C. & Massague, J. Molecular basis of metastasis. N. Engl. J. Med. 359, 2814–2823 (2008)

    CAS  Article  Google Scholar 

  2. 2

    Talmadge, J. E. & Fidler, I. J. AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Res. 70, 5649–5669 (2010)

    CAS  Article  Google Scholar 

  3. 3

    Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011)

    CAS  Article  Google Scholar 

  4. 4

    Valastyan, S. & Weinberg, R. A. MicroRNAs: crucial multi-tasking components in the complex circuitry of tumor metastasis. Cell Cycle 8, 3506–3512 (2009)

    CAS  Article  Google Scholar 

  5. 5

    Tavazoie, S. F. et al. Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451, 147–152 (2008)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Png, K. J. et al. MicroRNA-335 inhibits tumor reinitiation and is silenced through genetic and epigenetic mechanisms in human breast cancer. Genes Dev. 25, 226–231 (2011)

    CAS  Article  Google Scholar 

  7. 7

    Guo, C. et al. The noncoding RNA, miR-126, suppresses the growth of neoplastic cells by targeting phosphatidylinositol 3-kinase signaling and is frequently lost in colon cancers. Genes Chromosom. Cancer 47, 939–946 (2008)

    CAS  Article  Google Scholar 

  8. 8

    Feng, R. et al. miR-126 functions as a tumour suppressor in human gastric cancer. Cancer Lett. 298, 50–63 (2010)

    CAS  Article  Google Scholar 

  9. 9

    Gupta, G. P. et al. Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446, 765–770 (2007)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Jones, J. I. & Clemmons, D. R. Insulin-like growth factors and their binding proteins: biological actions. Endocr. Rev. 16, 3–34 (1995)

    CAS  PubMed  Google Scholar 

  11. 11

    Balogh, I. et al. Analysis of Gas6 in human platelets and plasma. Arterioscler. Thromb. Vasc. Biol. 25, 1280–1286 (2005)

    MathSciNet  CAS  Article  Google Scholar 

  12. 12

    Sather, S. et al. A soluble form of the Mer receptor tyrosine kinase inhibits macrophage clearance of apoptotic cells and platelet aggregation. Blood 109, 1026–1033 (2007)

    CAS  Article  Google Scholar 

  13. 13

    Minn, A. J. et al. Genes that mediate breast cancer metastasis to lung. Nature 436, 518–524 (2005)

    ADS  CAS  Article  Google Scholar 

  14. 14

    Kang, Y. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537–549 (2003)

    CAS  Article  Google Scholar 

  15. 15

    Yin, J. J. et al. TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J. Clin. Invest. 103, 197–206 (1999)

    CAS  Article  Google Scholar 

  16. 16

    Arnold, S. A. et al. Lack of host SPARC enhances vascular function and tumor spread in an orthotopic murine model of pancreatic carcinoma. Dis Model Mech 3, 57–72 (2010)

    CAS  Article  Google Scholar 

  17. 17

    Chin, K. et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 10, 529–541 (2006)

    CAS  Article  Google Scholar 

  18. 18

    Wang, Y. et al. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365, 671–679 (2005)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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.

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S.F.T. conceived the project and supervised all research. K.J.P., N.H, and S.F.T. wrote the manuscript. K.J.P., N.H. and S.F.T. designed the experiments. K.J.P., N.H. and M.Y. performed the experiments.

Corresponding author

Correspondence to Sohail F. Tavazoie.

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The authors declare no competing financial interests.

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This file contains Supplementary Figures 1-24 with legends, Supplementary Tables 1-9, a Supplementary Discussion and additional references. (PDF 4998 kb)

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Png, K., Halberg, N., Yoshida, M. et al. A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells. Nature 481, 190–194 (2012). https://doi.org/10.1038/nature10661

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