The perivascular niche regulates breast tumour dormancy

Cyrus M. Ghajar, Héctor Peinado, Hidetoshi Mori, Irina R. Matei, Kimberley J. Evason, Hélène Brazier, Dena Almeida, Antonius Koller, Katherine A. Hajjar, Didier Y R Stainier, Emily I. Chen, David Lyden, Mina J. Bissell

Research output: Contribution to journalArticle

501 Scopus citations

Abstract

In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumour cells (DTCs) are kept dormant, and what wakes them up, are fundamental problems in tumour biology. To address these questions, we used metastasis assays in mice and showed that dormant DTCs reside on microvasculature of lung, bone marrow and brain. We then engineered organotypic microvascular niches to determine whether endothelial cells directly influence breast cancer cell (BCC) growth. These models demonstrated that endothelial-derived thrombospondin-1 induces sustained BCC quiescence. This suppressive cue was lost in sprouting neovasculature; time-lapse analysis showed that sprouting vessels not only permit, but accelerate BCC outgrowth. We confirmed this surprising result in dormancy models and in zebrafish, and identified active TGF-β1 and periostin as tumour-promoting factors derived from endothelial tip cells. Our work reveals that stable microvasculature constitutes a dormant niche, whereas sprouting neovasculature sparks micrometastatic outgrowth.

Original languageEnglish (US)
Pages (from-to)807-817
Number of pages11
JournalNature Cell Biology
Volume15
Issue number7
DOIs
StatePublished - Jul 1 2013
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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    Ghajar, C. M., Peinado, H., Mori, H., Matei, I. R., Evason, K. J., Brazier, H., Almeida, D., Koller, A., Hajjar, K. A., Stainier, D. Y. R., Chen, E. I., Lyden, D., & Bissell, M. J. (2013). The perivascular niche regulates breast tumour dormancy. Nature Cell Biology, 15(7), 807-817. https://doi.org/10.1038/ncb2767