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

A. Bronisz, J. Godlewski, J. A. Wallace, A. S. Merchant, M. O. Nowicki, H. Mathsyaraja, R. Srinivasan, A. J. Trimboli, C. K. Martin, F. Li, L. Yu, S. A. Fernandez, T. Pécot, T. J. Rosol, S. Cory, M. Hallett, M. Park, M. G. Piper, C. B. Marsh, L. D. YeeR. E. Jimenez, G. Nuovo, S. E. Lawler, E. A. Chiocca, G. Leone, M. C. Ostrowski

Research output: Contribution to journalArticle

206 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)159-167
Number of pages9
JournalNature Cell Biology
Volume14
Issue number2
DOIs
StatePublished - Feb 2012

ASJC Scopus subject areas

  • Cell Biology

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    Bronisz, A., Godlewski, J., Wallace, J. A., Merchant, A. S., Nowicki, M. O., Mathsyaraja, H., Srinivasan, R., Trimboli, A. J., Martin, C. K., Li, F., Yu, L., Fernandez, S. A., Pécot, T., Rosol, T. J., Cory, S., Hallett, M., Park, M., Piper, M. G., Marsh, C. B., ... Ostrowski, M. C. (2012). Reprogramming of the tumour microenvironment by stromal PTEN-regulated miR-320. Nature Cell Biology, 14(2), 159-167. https://doi.org/10.1038/ncb2396