Interactions between cancer stem cells and their niche govern metastatic colonization

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Abstract

Metastatic growth in distant organs is the major cause of cancer mortality. The development of metastasis is a multistage process with several rate-limiting steps1. Although dissemination of tumour cells seems to be an early and frequent event2, the successful initiation of metastatic growth, a process termed ‘metastatic colonization’, is inefficient for many cancer types and is accomplished only by a minority of cancer cells that reach distant sites3,4. Prevalent target sites are characteristic of many tumour entities5, suggesting that inadequate support by distant tissues contributes to the inefficiency of the metastatic process. Here we show that a small population of cancer stem cells is critical for metastatic colonization, that is, the initial expansion of cancer cells at the secondary site, and that stromal niche signals are crucial to this expansion process. We find that periostin (POSTN), a component of the extracellular matrix, is expressed by fibroblasts in the normal tissue and in the stroma of the primary tumour. Infiltrating tumour cells need to induce stromal POSTN expression in the secondary target organ (in this case lung) to initiate colonization. POSTN is required to allow cancer stem cell maintenance, and blocking its function prevents metastasis. POSTN recruits Wnt ligands and thereby increases Wnt signalling in cancer stem cells. We suggest that the education of stromal cells by infiltrating tumour cells is an important step in metastatic colonization and that preventing de novo niche formation may be a novel strategy for the treatment of metastatic disease.

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Figure 1: Cancer stem cells initiate metastasis.
Figure 2: POSTN is a stromal niche component that is induced on metastasis formation.
Figure 3: POSTN is required for metastatic colonization by affecting CSC maintenance.
Figure 4: POSTN promotes stem cell maintenance and metastasis formation by augmenting Wnt signalling.

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Acknowledgements

We are grateful to U. Koch for advice on FACS, to M. Moniatte for advice on mass spectrometry and to S. Leuba for technical assistance with histology. I.M., E.S., A.S.-M. and J.H. were supported in part by the Swiss League against Cancer, the SNF, the NCCR in Molecular Oncology and the Anna Fuller Fund. J.H. holds the EPFL chair for Signal Transduction in Oncogenesis sponsored by Debiopharm.

Author information

I.M., A.S.-M. and J.H. designed and performed most of the experiments, analysed data and prepared the manuscript; E.S. and H.P. performed experiments; H.-A.L. performed experiments and analysed data; J.-F.D. provided clinical samples; and J.H. designed and supervised the study.

Correspondence to Joerg Huelsken.

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The authors declare no competing financial interests.

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Malanchi, I., Santamaria-Martínez, A., Susanto, E. et al. Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481, 85–89 (2012) doi:10.1038/nature10694

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