Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs


We report that breast cancer cells that infiltrate the lungs support their own metastasis-initiating ability by expressing tenascin C (TNC). We find that the expression of TNC, an extracellular matrix protein of stem cell niches, is associated with the aggressiveness of pulmonary metastasis. Cancer cell–derived TNC promotes the survival and outgrowth of pulmonary micrometastases. TNC enhances the expression of stem cell signaling components, musashi homolog 1 (MSI1) and leucine-rich repeat–containing G protein–coupled receptor 5 (LGR5). MSI1 is a positive regulator of NOTCH signaling, whereas LGR5 is a target gene of the WNT pathway. TNC modulation of stem cell signaling occurs without affecting the expression of transcriptional enforcers of the stem cell phenotype and pluripotency, namely nanog homeobox (NANOG), POU class 5 homeobox 1 (POU5F1), also known as OCT4, and SRY-box 2 (SOX2). TNC protects MSI1-dependent NOTCH signaling from inhibition by signal transducer and activator of transcription 5 (STAT5), and selectively enhances the expression of LGR5 as a WNT target gene. Cancer cell–derived TNC remains essential for metastasis outgrowth until the tumor stroma takes over as a source of TNC. These findings link TNC to pathways that support the fitness of metastasis-initiating breast cancer cells and highlight the relevance of TNC as an extracellular matrix component of the metastatic niche.

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Figure 1: TNC expression in lung metastatic foci and association with lung relapse.
Figure 2: Cancer cell–derived TNC mediates resistance to apoptosis in micrometastasis.
Figure 3: Expression of TNC and stem cell markers in oncospheres.
Figure 4: Regulation of oncosphere growth, MSI1 and LGR5 by TNC.
Figure 5: TNC enhances WNT and NOTCH signaling in breast cancer cells.
Figure 6: TNC association with STAT5 and Musashi in breast cancer metastasis.


  1. 1

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

    Article  Google Scholar 

  2. 2

    Cameron, M.D. et al. Temporal progression of metastasis in lung: cell survival, dormancy, and location dependence of metastatic inefficiency. Cancer Res. 60, 2541–2546 (2000).

    CAS  PubMed  Google Scholar 

  3. 3

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

    CAS  Article  Google Scholar 

  4. 4

    Hynes, R.O. The extracellular matrix: not just pretty fibrils. Science 326, 1216–1219 (2009).

    CAS  Article  Google Scholar 

  5. 5

    Barkan, D., Green, J.E. & Chambers, A.F. Extracellular matrix: a gatekeeper in the transition from dormancy to metastatic growth. Eur. J. Cancer 46, 1181–1188 (2010).

    CAS  Article  Google Scholar 

  6. 6

    Anan, K. et al. Disparities in the survival improvement of recurrent breast cancer. Breast Cancer 17, 48–55 (2010).

    Article  Google Scholar 

  7. 7

    Minn, A.J. et al. Genes that mediate breast cancer metastasis to lung. Nature 436, 518–524 (2005).

    CAS  Article  Google Scholar 

  8. 8

    Tavazoie, S.F. et al. Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451, 147–152 (2008).

    CAS  Article  Google Scholar 

  9. 9

    Gupta, G.P. et al. Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446, 765–770 (2007).

    CAS  Article  Google Scholar 

  10. 10

    Kim, M.Y. et al. Tumor self-seeding by circulating cancer cells. Cell 139, 1315–1326 (2009).

    Article  Google Scholar 

  11. 11

    Kii, I. et al. Incorporation of tenascin-C into the extracellular matrix by periostin underlies an extracellular meshwork architecture. J. Biol. Chem. 285, 2028–2039 (2010).

    CAS  Article  Google Scholar 

  12. 12

    Orend, G. & Chiquet-Ehrismann, R. Tenascin-C induced signaling in cancer. Cancer Lett. 244, 143–163 (2006).

    CAS  Article  Google Scholar 

  13. 13

    von Holst, A. Tenascin C in stem cell niches: redundant, permissive or instructive? Cells Tissues Organs 188, 170–177 (2008).

    CAS  Article  Google Scholar 

  14. 14

    Artavanis-Tsakonas, S., Rand, M.D. & Lake, R.J. Notch signaling: cell fate control and signal integration in development. Science 284, 770–776 (1999).

    CAS  Article  Google Scholar 

  15. 15

    Logan, C.Y. & Nusse, R. The Wnt signaling pathway in development and disease. Annu. Rev. Cell Dev. Biol. 20, 781–810 (2004).

    CAS  Article  Google Scholar 

  16. 16

    Hermann, P.C. et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1, 313–323 (2007).

    CAS  Article  Google Scholar 

  17. 17

    Joyce, J.A. & Pollard, J.W. Microenvironmental regulation of metastasis. Nat. Rev. Cancer 9, 239–252 (2009).

    CAS  Article  Google Scholar 

  18. 18

    Deryugina, E.I. & Bourdon, M.A. Tenascin mediates human glioma cell migration and modulates cell migration on fibronectin. J. Cell Sci. 109, 643–652 (1996).

    CAS  PubMed  Google Scholar 

  19. 19

    Ishihara, A., Yoshida, T., Tamaki, H. & Sakakura, T. Tenascin expression in cancer cells and stroma of human breast cancer and its prognostic significance. Clin. Cancer Res. 1, 1035–1041 (1995).

    CAS  PubMed  Google Scholar 

  20. 20

    Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004).

    CAS  Article  Google Scholar 

  21. 21

    Garcion, E., Halilagic, A., Faissner, A. & ffrench-Constant, C. Generation of an environmental niche for neural stem cell development by the extracellular matrix molecule tenascin C. Development 131, 3423–3432 (2004).

    CAS  Article  Google Scholar 

  22. 22

    Dontu, G. et al. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 17, 1253–1270 (2003).

    CAS  Article  Google Scholar 

  23. 23

    Ponti, D. et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res. 65, 5506–5511 (2005).

    CAS  Article  Google Scholar 

  24. 24

    Chambers, I. et al. Nanog safeguards pluripotency and mediates germline development. Nature 450, 1230–1234 (2007).

    CAS  Article  Google Scholar 

  25. 25

    Nichols, J. et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95, 379–391 (1998).

    CAS  Article  Google Scholar 

  26. 26

    Adewumi, O. et al. Characterization of human embryonic stem cell lines by the International Stem Cell Initiative. Nat. Biotechnol. 25, 803–816 (2007).

    CAS  Article  Google Scholar 

  27. 27

    Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    CAS  Article  Google Scholar 

  28. 28

    Okano, H. et al. Function of RNA-binding protein Musashi-1 in stem cells. Exp. Cell Res. 306, 349–356 (2005).

    CAS  Article  Google Scholar 

  29. 29

    Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).

    CAS  Article  Google Scholar 

  30. 30

    Kouros-Mehr, H., Slorach, E.M., Sternlicht, M.D. & Werb, Z. GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell 127, 1041–1055 (2006).

    CAS  Article  Google Scholar 

  31. 31

    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).

    CAS  Article  Google Scholar 

  32. 32

    Fillmore, C.M. & Kuperwasser, C. Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res. 10, R25 (2008).

    Article  Google Scholar 

  33. 33

    Imai, T. et al. The neural RNA-binding protein Musashi1 translationally regulates mammalian numb gene expression by interacting with its mRNA. Mol. Cell. Biol. 21, 3888–3900 (2001).

    CAS  Article  Google Scholar 

  34. 34

    Bouras, T. et al. Notch signaling regulates mammary stem cell function and luminal cell-fate commitment. Cell Stem Cell 3, 429–441 (2008).

    CAS  Article  Google Scholar 

  35. 35

    Lim, E. et al. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat. Med. 15, 907–913 (2009).

    CAS  Article  Google Scholar 

  36. 36

    Molyneux, G. et al. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 7, 403–417 (2010).

    CAS  Article  Google Scholar 

  37. 37

    Wagner, K.U. & Rui, H. Jak2/Stat5 signaling in mammogenesis, breast cancer initiation and progression. J. Mammary Gland Biol. Neoplasia 13, 93–103 (2008).

    Article  Google Scholar 

  38. 38

    Chammas, R., Taverna, D., Cella, N., Santos, C. & Hynes, N.E. Laminin and tenascin assembly and expression regulate HC11 mouse mammary cell differentiation. J. Cell Sci. 107, 1031–1040 (1994).

    CAS  PubMed  Google Scholar 

  39. 39

    Sandberg, E.M. & Sayeski, P.P. Jak2 tyrosine kinase mediates oxidative stress-induced apoptosis in vascular smooth muscle cells. J. Biol. Chem. 279, 34547–34552 (2004).

    CAS  Article  Google Scholar 

  40. 40

    Müller, J., Sperl, B., Reindl, W., Kiessling, A. & Berg, T. Discovery of chromone-based inhibitors of the transcription factor STAT5. ChemBioChem 9, 723–727 (2008).

    Article  Google Scholar 

  41. 41

    Ruiz, C. et al. Growth promoting signaling by tenascin-C. Cancer Res. 64, 7377–7385 (2004).

    CAS  Article  Google Scholar 

  42. 42

    Kang, Y. et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537–549 (2003).

    CAS  Article  Google Scholar 

  43. 43

    Bos, P.D. et al. Genes that mediate breast cancer metastasis to the brain. Nature 459, 1005–1009 (2009).

    CAS  Article  Google Scholar 

  44. 44

    Eilon, T. & Barash, I. Distinct gene-expression profiles characterize mammary tumors developed in transgenic mice expressing constitutively active and C-terminally truncated variants of STAT5. BMC Genomics 10, 231 (2009).

    Article  Google Scholar 

  45. 45

    Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).

    CAS  Article  Google Scholar 

  46. 46

    Ioachim, E. et al. Immunohistochemical expression of extracellular matrix components tenascin, fibronectin, collagen type IV and laminin in breast cancer: their prognostic value and role in tumour invasion and progression. Eur. J. Cancer 38, 2362–2370 (2002).

    CAS  Article  Google Scholar 

  47. 47

    Casali, A. & Batlle, E. Intestinal stem cells in mammals and Drosophila. Cell Stem Cell 4, 124–127 (2009).

    CAS  Article  Google Scholar 

  48. 48

    Lin, S.Y. et al. β-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression. Proc. Natl. Acad. Sci. USA 97, 4262–4266 (2000).

    CAS  Article  Google Scholar 

  49. 49

    Farnie, G. et al. Novel cell culture technique for primary ductal carcinoma in situ: role of Notch and epidermal growth factor receptor signaling pathways. J. Natl. Cancer Inst. 99, 616–627 (2007).

    CAS  Article  Google Scholar 

  50. 50

    Wang, X.Y. et al. Musashi1 regulates breast tumor cell proliferation and is a prognostic indicator of poor survival. Mol. Cancer 9, 221 (2010).

    Article  Google Scholar 

  51. 51

    Reedijk, M. et al. High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res. 65, 8530–8537 (2005).

    CAS  Article  Google Scholar 

  52. 52

    Pece, S. et al. Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. J. Cell Biol. 167, 215–221 (2004).

    CAS  Article  Google Scholar 

  53. 53

    Cotarla, I. et al. Stat5a is tyrosine phosphorylated and nuclear localized in a high proportion of human breast cancers. Int. J. Cancer 108, 665–671 (2004).

    CAS  Article  Google Scholar 

  54. 54

    Nevalainen, M.T. et al. Signal transducer and activator of transcription-5 activation and breast cancer prognosis. J. Clin. Oncol. 22, 2053–2060 (2004).

    CAS  Article  Google Scholar 

  55. 55

    Saga, Y., Yagi, T., Ikawa, Y., Sakakura, T. & Aizawa, S. Mice develop normally without tenascin. Genes Dev. 6, 1821–1831 (1992).

    CAS  Article  Google Scholar 

  56. 56

    Mackie, E.J. & Tucker, R.P. The tenascin-C knockout revisited. J. Cell Sci. 112, 3847–3853 (1999).

    CAS  PubMed  Google Scholar 

  57. 57

    Gomis, R.R., Alarcon, C., Nadal, C., Van Poznak, C. & Massague, J. C/EBPβ at the core of the TGFβ cytostatic response and its evasion in metastatic breast cancer cells. Cancer Cell 10, 203–214 (2006).

    CAS  Article  Google Scholar 

  58. 58

    Smid, M. et al. Subtypes of breast cancer show preferential site of relapse. Cancer Res. 68, 3108–3114 (2008).

    CAS  Article  Google Scholar 

  59. 59

    Zhang, X.H. et al. Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell 16, 67–78 (2009).

    CAS  Article  Google Scholar 

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We thank J. Kim and E. Montalvo for technical support. This work was funded by grant CA94060 from the US National Institutes of Health (J.M.), the Hearst Foundation and the Alan and Sandra Gerry Metastasis Research Initiative. S.A. is supported by a Department of Defense Era of Hope postdoctoral fellowship. E.B. is a recipient of the Exceptional Project Award from the Breast Cancer Alliance. J.M. is an investigator of the Howard Hughes Medical Institute.

Author information




T.O. and J.M. designed experiments, analyzed data and wrote the manuscript. J.M. supervised research. T.O. carried out experiments. S.A. carried out immunostaining and helped with pathway analyses. X.H.-F.Z. carried out bioinformatics analyses. S.V. carried out intracardiac injections and assisted with bone and brain metastasis assays. S.F.T. helped with miRNA analysis. P.G.M. and R.J.D. oversaw collection of clinical samples. K.M.-T. supervised histological staining and analysis. E.B. obtained and evaluated human breast cancer tissue sections. All authors discussed the results and commented on the manuscript.

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Correspondence to Joan Massagué.

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

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