Interactions between cancer stem cells and their niche govern metastatic colonization

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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.


  1. 1

    Chambers, A. F., Groom, A. C. & MacDonald, I. C. Dissemination and growth of cancer cells in metastatic sites. Nature Rev. Cancer 2, 563–572 (2002)

  2. 2

    Hüsemann, Y. et al. Systemic spread is an early step in breast cancer. Cancer Cell 13, 58–68 (2008)

  3. 3

    Kouros-Mehr, H. et al. GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model. Cancer Cell 13, 141–152 (2008)

  4. 4

    Nguyen, D. X., Bos, P. D. & Massague, J. Metastasis: from dissemination to organ-specific colonization. Nature Rev. Cancer 9, 274–284 (2009)

  5. 5

    Hess, K. R. et al. Metastatic patterns in adenocarcinoma. Cancer 106, 1624–1633 (2006)

  6. 6

    Lin, E. Y. et al. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am. J. Pathol. 163, 2113–2126 (2003)

  7. 7

    Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003)

  8. 8

    Reya, T. & Clevers, H. Wnt signalling in stem cells and cancer. Nature 434, 843–850 (2005)

  9. 9

    Cho, R. W. et al. Isolation and molecular characterization of cancer stem cells in MMTV-Wnt-1 murine breast tumors. Stem Cells 26, 364–371 (2008)

  10. 10

    Shackleton, M. et al. Generation of a functional mammary gland from a single stem cell. Nature 439, 84–88 (2006)

  11. 11

    Stingl, J. et al. Purification and unique properties of mammary epithelial stem cells. Nature 439, 993–997 (2006)

  12. 12

    Liu, J. C., Deng, T., Lehal, R. S., Kim, J. & Zacksenhaus, E. Identification of tumorsphere- and tumor-initiating cells in HER2/Neu-induced mammary tumors. Cancer Res. 67, 8671–8681 (2007)

  13. 13

    Zhang, M. et al. Identification of tumor-initiating cells in a p53-null mouse model of breast cancer. Cancer Res. 68, 4674–4682 (2008)

  14. 14

    Podsypanina, K. et al. Seeding and propagation of untransformed mouse mammary cells in the lung. Science 321, 1841–1844 (2008)

  15. 15

    Vermeulen, L. et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nature Cell Biol. 12, 468–476 (2010)

  16. 16

    Visvader, J. E. & Lindeman, G. J. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nature Rev. Cancer 8, 755–768 (2008)

  17. 17

    Psaila, B. & Lyden, D. The metastatic niche: adapting the foreign soil. Nature Rev. Cancer 9, 285–293 (2009)

  18. 18

    Takeshita, S., Kikuno, R., Tezuka, K. & Amann, E. Osteoblast-specific factor 2: cloning of a putative bone adhesion protein with homology with the insect protein fasciclin I. Biochem. J. 294, 271–278 (1993)

  19. 19

    Shimazaki, M. & Kudo, A. Impaired capsule formation of tumors in periostin-null mice. Biochem. Biophys. Res. Commun. 367, 736–742 (2008)

  20. 20

    Oka, T. et al. Genetic manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular remodeling. Circ. Res. 101, 313–321 (2007)

  21. 21

    Rios, H. et al. Periostin null mice exhibit dwarfism, incisor enamel defects, and an early-onset periodontal disease-like phenotype. Mol. Cell. Biol. 25, 11131–11144 (2005)

  22. 22

    Zhao, W. et al. Suppression of in vivo tumorigenicity of rat hepatoma cell line KDH-8 cells by soluble TGF-beta receptor type II. Cancer Immunol. Immunother. 51, 381–388 (2002)

  23. 23

    Muraoka, R. S. et al. Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases. J. Clin. Invest. 109, 1551–1559 (2002)

  24. 24

    Pece, S. et al. Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell 140, 62–73 (2010)

  25. 25

    Milovanovic, T. et al. Expression of Wnt genes and frizzled 1 and 2 receptors in normal breast epithelium and infiltrating breast carcinoma. Int. J. Oncol. 25, 1337–1342 (2004)

  26. 26

    Zeng, Y. A. & Nusse, R. Wnt proteins are self-renewal factors for mammary stem cells and promote their long-term expansion in culture. Cell Stem Cell 6, 568–577 (2010)

  27. 27

    Malanchi, I. et al. Cutaneous cancer stem cell maintenance is dependent on β-catenin signaling. Nature 452, 650–653 (2008)

  28. 28

    Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009)

  29. 29

    Wels, J., Kaplan, R. N., Rafii, S. & Lyden, D. Migratory neighbors and distant invaders: tumor-associated niche cells. Genes Dev. 22, 559–574 (2008)

  30. 30

    Oskarsson, T. et al. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nature Med. 17, 867–874 (2011)

  31. 31

    Guy, C. T., Cardiff, R. D. & Muller, W. J. Induction of mammary tumours by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol. Cell. Biol. 12, 954–961 (1992)

  32. 32

    Tsukamoto, A. S., Grosschedl, R., Guzman, R. C., Parslow, T. & Varmus, H. E. Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell 55, 619–625 (1988)

  33. 33

    Okabe, M., Ikawa, M., Kominami, K., Nakanishi, T. & Nishimune, Y. ‘Green mice’ as a source of ubiquitous green cells. FEBS Lett. 407, 313–319 (1997)

  34. 34

    Jeannet, G. et al. Long-term, multilineage hematopoiesis occurs in the combined absence of β-catenin and γ-catenin. Blood 111, 142–149 (2008)

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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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