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Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320

Nature Cell Biology volume 14, pages 159–167 (2012)Cite this article

Abstract

PTEN (Phosphatase and tensin homolog deleted on chromosome 10) expression in stromal fibroblasts suppresses epithelial mammary tumours, but the underlying molecular mechanisms remain unknown. Using proteomic and expression profiling, we show that Pten loss from mammary stromal fibroblasts activates an oncogenic secretome that orchestrates the transcriptional reprogramming of other cell types in the microenvironment. Downregulation of miR-320 and upregulation of one of its direct targets, ETS2 (v-ets erythroblastosis virus E26 oncogene homolog 2) are critical events in Pten-deleted stromal fibroblasts responsible for inducing this oncogenic secretome, which in turn promotes tumour angiogenesis and tumour-cell invasion. Expression of the Pten–miR-320–Ets2-regulated secretome distinguished human normal breast stroma from tumour stroma and robustly correlated with recurrence in breast cancer patients. This work reveals miR-320 as a critical component of the Pten tumour-suppressor axis that acts in stromal fibroblasts to reprogramme the tumour microenvironment and curtail tumour progression.

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Figure 1: miR-320 is a PTEN target in fibroblasts that suppresses tumour growth.
Figure 2: miR-320 and PTEN are co-expressed in human tumour stroma.
Figure 3: Pten and miR-320 in fibroblasts control tumour-cell migration and growth.
Figure 4: miR-320 regulates the secretome of MMFs.
Figure 5: Identification and characterization of Ets2, Mmp9 and Emilin2 as bona fide targets of miR-320.
Figure 6: The miR-320 secretome profile separates human breast normal and cancer stroma (tumour type, TT) and predicts patient outcome.

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Acknowledgements

We thank Kara Batte for technical assistance with the microRNA platform, Rumeysa Biyik for bioinformatics assistance, Abdel-Rasoul Mahmoud for statistical assistance and the Ohio State University Human Tissue Resource Network and the Ohio State University Comprehensive Cancer Center Microarray, Nucleic Acids, Proteomic Shared Facilities for technical assistance. This work was funded by grants from the National Institutes of Health to M.C.O. (R01CA053271, P01CA097189) and to G.L. (R01CA85619, R01HD47470, P01CA097189) and from the Komen Breast Cancer Foundation and Evelyn Simmers Charitable Trust to M.C.O.

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Authors and Affiliations

  1. Tumor Microenvironment Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA

    A. Bronisz, G. Leone & M. C. Ostrowski

  2. Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA

    A. Bronisz, J. A. Wallace, A.S. Merchant, H. Mathsyaraja, R. Srinivasan, C. K. Martin, F. Li & M. C. Ostrowski

  3. Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Medical Center and James Comprehensive Cancer Center, Columbus, Ohio 43210, USA

    J. Godlewski, M.O. Nowicki, S. E. Lawler & E. A. Chiocca

  4. Department of Molecular Genetics, College of Biological Sciences, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210, USA

    A. J. Trimboli, F. Li, T. Pécot & G. Leone

  5. Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, Ohio 43210, USA

    A. J. Trimboli, T. Pécot & G. Leone

  6. Center for Biostatistics, Office of Health Sciences, The Ohio State University, Columbus, Ohio 43210, USA

    L. Yu & S. A. Fernandez

  7. The Ohio State University Computer Science and Engineering, The Ohio State University Biomedical Informatics, The Ohio State University, Columbus, Ohio 43210, USA

    T. Pécot

  8. Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio 43210, USA

    T. J. Rosol

  9. McGill Centre for Bioinformatics, McGill University, Montreal, Quebec, H3A0B1, Canada

    S. Cory & M. Hallett

  10. Department of Biochemistry, Rosalind and Morris Goodman Cancer Center University, Montreal, Quebec, H3A0B, Canada

    S. Cory, M. Hallett & M. Park

  11. Department of Oncology, McGill University, Quebec, H3A 1A1, Canada

    M. Park

  12. Division of Pulmonary, Department of Internal Medicine, Allergy, Critical Care, and Sleep Medicine, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio 43210, USA

    M. G. Piper & C. B. Marsh

  13. Department of Surgery, School of Medicine, The Ohio State University, Columbus, Ohio 43210, USA

    L. D. Yee

  14. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA

    R. E. Jimenez

  15. Department of Pathology, The Ohio State University Medical Center and James Comprehensive Cancer Center, Columbus, Ohio 43210, USA

    G. Nuovo

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  1. A. Bronisz
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Contributions

M.C.O. and G.L. designed and supervised this study, analysed data and helped write and edit the manuscript. A.B. and J.G. designed and carried out experiments, collected and analysed data and co-wrote the paper. J.A.W., H.M., R.S., A.J.T. and F.L. assisted technically with experiments, and collected and analysed data. M.O.N. assisted with fluorescent and confocal microscopy and immunohistochemistry. L.Y. and S.A.F. contributed to the statistical analyses of data and writing the manuscript. A.S.M., S.C., M.H., M.P. and T.P. contributed to the analysis and comparison of mouse and human profile data. M.G.P. and C.B.M. contributed to the analysis of microRNA data and writing the manuscript. C.K.M., L.D.Y., R.E.J., G.N. and T.J.R. contributed to the histopathological analysis of human samples and writing the manuscript. S.E.L. and E.A.C. contributed to the data analysis and writing the manuscript.

Corresponding authors

Correspondence to G. Leone or M. C. Ostrowski.

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Bronisz, A., Godlewski, J., Wallace, J. et al. Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320. Nat Cell Biol 14, 159–167 (2012). https://doi.org/10.1038/ncb2396

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