Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis

Nature Cell Biology volume 15, pages 677–687 (2013)Cite this article

Subjects

Abstract

Increased stromal collagen deposition in human breast tumours correlates with metastases. We show that activation of the collagen I receptor DDR2 (discoidin domain receptor 2) regulates SNAIL1 stability by stimulating ERK2 activity, in a Src-dependent manner. Activated ERK2 directly phosphorylates SNAIL1, leading to SNAIL1 nuclear accumulation, reduced ubiquitylation and increased protein half-life. DDR2-mediated stabilization of SNAIL1 promotes breast cancer cell invasion and migration in vitro, and metastasis in vivo. DDR2 expression was observed in most human invasive ductal breast carcinomas studied, and was associated with nuclear SNAIL1 and absence of E-cadherin expression. We propose that DDR2 maintains SNAIL1 level and activity in tumour cells that have undergone epithelial–mesenchymal transition (EMT), thereby facilitating continued tumour cell invasion through collagen-I-rich extracellular matrices by sustaining the EMT phenotype. As such, DDR2 could be an RTK (receptor tyrosine kinase) target for the treatment of breast cancer metastasis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: DDR2 stabilizes the cellular SNAIL1 level, post-transcriptionally.
Figure 2: Collagen-I-induced stabilization of SNAIL1 requires DDR2.
Figure 3: DDR2 influences breast cancer cell migration in vitro and metastases in vivo.
Figure 4: Collagen fibre alignment at tumour/ECM boundary.
Figure 5: DDR2 stabilizes SNAIL1 through ERK2 phosphorylation of SNAIL1.
Figure 6: ERK2 phosphorylation of SNAIL1 results in nuclear accumulation and diminished ubiquitylation.
Figure 7: Delineation of the intracellular signalling pathway whereby DDR2 leads to SNAIL1 stabilization and tumour cell invasion/migration.
Figure 8: DDR2 expression is present in most human invasive (Inv.) ductal breast cancers and correlates with the presence of nuclear SNAIL1 and loss of E-cadherin expression.

Similar content being viewed by others

References

  1. Kauppila, S., Stenback, F., Risteli, J., Jukkola, A. & Risteli, L. Aberrant type I and type III collagen gene expression in human breast cancer in vivo. J. Pathol. 186, 262–268 (1998).

    Article  CAS  Google Scholar 

  2. Provenzano, P. P. et al. Collagen density promotes mammary tumor initiation and progression. BMC Med. 6, 11–26 (2008).

    Article  Google Scholar 

  3. Paszek, M. J. et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 8, 241–254 (2005).

    Article  CAS  Google Scholar 

  4. Conklin, M. W. et al. Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am. J. Pathol. 178, 1221–1232 (2011).

    Article  Google Scholar 

  5. Valiathan, R. R., Marco, M., Leitinger, B., Kleer, C. G. & Fridman, R. Discoidin domain receptor tyrosine kinases: new players in cancer progression. Cancer Metastasis Rev. 31, 295–321 (2012).

    Article  CAS  Google Scholar 

  6. Leitinger, B. Transmembrane collagen receptors. Annu. Rev. Cell Dev. Biol. 27, 265–290 (2011).

    Article  CAS  Google Scholar 

  7. Perou, C. M. Molecular stratification of triple-negative breast cancers. Oncologist 15 (Suppl. 5), 39–48 (2010).

    Article  CAS  Google Scholar 

  8. Thiery, J. P., Acloque, H., Huang, R. Y. & Nieto, M. A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).

    Article  CAS  Google Scholar 

  9. Moody, S. E. et al. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 8, 197–209 (2005).

    Article  CAS  Google Scholar 

  10. Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004).

    Article  CAS  Google Scholar 

  11. Drasin, D. J., Robin, T. P. & Ford, H. L. Breast cancer epithelial-to-mesenchymal transition: examining the functional consequences of plasticity. Breast Cancer Res. 13, 226–239 (2011).

    Article  Google Scholar 

  12. Tran, D. D., Corsa, C. A., Biswas, H., Aft, R. L. & Longmore, G. D. Temporal and spatial cooperation of Snail1 and Twist1 during epithelial-mesenchymal transition predicts for human breast cancer recurrence. Mol. Cancer Res. 9, 1644–1657 (2011).

    Article  CAS  Google Scholar 

  13. Franci, C. et al. Expression of Snail protein in tumor–stroma interface. Oncogene 25, 5134–5144 (2006).

    Article  CAS  Google Scholar 

  14. Zhou, B. P. et al. Dual regulation of Snail by GSK- 3β-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat. Cell Biol. 6, 931–940 (2004).

    Article  CAS  Google Scholar 

  15. Yook, J. I. et al. A Wnt-Axin2-GSK3β cascade regulates Snail1 activity in breast cancer cells. Nat. Cell Biol. 8, 1398–1406 (2006).

    Article  CAS  Google Scholar 

  16. Zhang, K. et al. Lats2 kinase potentiates Snail1 activity by promoting nuclear retention upon phosphorylation. EMBO J. 31, 29–43 (2011).

    Article  Google Scholar 

  17. Egeblad, M., Rasch, M. G. & Weaver, V. M. Dynamic interplay between the collagen scaffold and tumor evolution. Curr. Opin. Cell Biol. 22, 697–706 (2010).

    Article  CAS  Google Scholar 

  18. Schedin, P. & Keely, P. J. Mammary gland ECM remodeling, stiffness, and mechanosignaling in normal development and tumor progression. Cold Spring Harbor Perspect. Biol. 3, a003228 (2011).

    Article  Google Scholar 

  19. Walker, R. A. The complexities of breast cancer desmoplasia. Breast Cancer Res. 3, 143–145 (2001).

    Article  CAS  Google Scholar 

  20. Kreike, B. et al. Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res. 9, R65 (2007).

    Article  Google Scholar 

  21. Provenzano, P. P. et al. Collagen reorganization at the tumor–stromal interface facilitates local invasion. BMC Med. 4, 38–54 (2006).

    Article  Google Scholar 

  22. Ferri, N., Carragher, N. O. & Raines, E. W. Role of discoidin domain receptors 1 and 2 in human smooth muscle cell-mediated collagen remodeling: potential implications in atherosclerosis and lymphangioleiomyomatosis. Am. J. Pathol. 164, 1575–1585 (2004).

    Article  CAS  Google Scholar 

  23. Flynn, L. A., Blissett, A. R., Calomeni, E. P. & Agarwal, G. Inhibition of collagen fibrillogenesis by cells expressing soluble extracellular domains of DDR1 and DDR2. J. Mol. Biol. 395, 533–543 (2010).

    Article  CAS  Google Scholar 

  24. Sivakumar, L. & Agarwal, G. The influence of discoidin domain receptor 2 on the persistence length of collagen type I fibres. Biomaterials 31, 4802–4808 (2010).

    Article  CAS  Google Scholar 

  25. MacPherson, M. R. et al. Phosphorylation of serine 11 and serine 92 as new positive regulators of human Snail1 function: potential involvement of casein kinase-2 and the cAMP-activated kinase protein kinase A. Mol. Biol. Cell 21, 244–253 (2010).

    Article  CAS  Google Scholar 

  26. Shin, S., Dimitri, C. A., Yoon, S. O., Dowdle, W. & Blenis, J. ERK2 but not ERK1 induces epithelial-to-mesenchymal transformation via DEF motif-dependent signaling events. Mol. Cell 38, 114–127 (2010).

    Article  CAS  Google Scholar 

  27. Jacobs, D., Glossip, D., Xing, H., Muslin, A. J. & Kornfeld, K. Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase. Genes Dev. 13, 163–175 (1999).

    Article  CAS  Google Scholar 

  28. Feng, Y. et al. A multifunctional lentiviral-based gene knockdown with concurrent rescue that controls for off-target effects of RNAi. Genom. Proteom. Bioinform. 8, 238–245 (2010).

    Article  CAS  Google Scholar 

  29. Ikeda, K. et al. Discoidin domain receptor 2 interacts with Src and Shc following its activation by type I collagen. J. Biol. Chem. 277, 19206–19212 (2002).

    Article  CAS  Google Scholar 

  30. Ding, Q. et al. Erk associates with and primes GSK- 3β for its inactivation resulting in upregulation of β-catenin. Mol. Cell 19, 159–170 (2005).

    Article  CAS  Google Scholar 

  31. Desbois-Mouthon, C. et al. Insulin and IGF-1 stimulate the β-catenin pathway through two signalling cascades involving GSK- 3β inhibition and Ras activation. Oncogene 20, 252–259 (2001).

    Article  CAS  Google Scholar 

  32. Ota, I., Li, X. Y., Hu, Y. & Weiss, S. J. Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1. Proc. Natl Acad. Sci. USA 106, 20318–20323 (2009).

    Article  CAS  Google Scholar 

  33. Rowe, R. G. et al. Mesenchymal cells reactivate Snail1 expression to drive three-dimensional invasion programs. J. Cell Biol. 184, 399–408 (2009).

    Article  CAS  Google Scholar 

  34. Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).

    Article  Google Scholar 

  35. Provenzano, P. P., Inman, D. R., Eliceiri, K. W. & Keely, P. J. Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK-ERK linkage. Oncogene 28, 4326–4343 (2009).

    Article  CAS  Google Scholar 

  36. White, D. E. et al. Targeted disruption of β1 integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. Cancer Cell 6, 159–170 (2004).

    Article  CAS  Google Scholar 

  37. Mariotti, A. et al. EGF-R signaling through Fyn kinase disrupts the function of integrin α6β4 at hemidesmosomes: role in epithelial cell migration and carcinoma invasion. J. Cell Biol. 155, 447–458 (2001).

    Article  CAS  Google Scholar 

  38. Soung, Y. H., Clifford, J. L. & Chung, J. Crosstalk between integrin and receptor tyrosine kinase signaling in breast carcinoma progression. BMB Rep. 43, 311–318 (2010).

    Article  CAS  Google Scholar 

  39. Aiello, E. J., Buist, D. S., White, E. & Porter, P. L. Association between mammographic breast density and breast cancer tumor characteristics. Cancer Epid. Biom. Prev. 14, 662–668 (2005).

    Article  Google Scholar 

  40. McDaniel, S. M. et al. Remodeling of the mammary microenvironment after lactation promotes breast tumor cell metastasis. Am. J. Pathol. 168, 608–620 (2006).

    Article  CAS  Google Scholar 

  41. Sharp, T. V. et al. The chromosome 3p21.3-encoded gene, LIMD1, is a critical tumor suppressor involved in human lung cancer development. Proc. Natl Acad. Sci. USA 105, 19932–19937 (2008).

    Article  CAS  Google Scholar 

  42. Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−ΔΔC(T)) method. Methods 25, 402–408 (2001).

    Article  CAS  Google Scholar 

  43. Noordeen, N. A., Carafoli, F., Hohenester, E., Horton, M. A. & Leitinger, B. A transmembrane leucine zipper is required for activation of the dimeric receptor tyrosine kinase DDR1. J. Biol. Chem. 281, 22744–22751 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH grant P50CA94056 to the Imaging Core of the Siteman Cancer Center at Washington University, and NIH grants GM080673 and CA143868, and Susan G. Komen for the Cure KG110889 to G.D.L. C.A.C. was supported by NIH grant F31CA165729.

Author information

Authors and Affiliations

  1. BRIGHT Institute, Washington University, St Louis, Missouri 63110, USA

    Kun Zhang, Callie A. Corsa, Julie L. Prior, David Piwnica-Worms & Gregory D. Longmore

  2. Department of Cell Biology and Physiology, Washington University, St Louis, Missouri 63110, USA

    Kun Zhang, Callie A. Corsa, David Piwnica-Worms & Gregory D. Longmore

  3. Department of Medicine, Washington University, St Louis, Missouri 63110, USA

    Callie A. Corsa & Gregory D. Longmore

  4. Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA

    Suzanne M. Ponik & Patricia J. Keely

  5. Molecular Imaging Center in the Mallinckrodt Institute of Radiology, Washington University, St Louis, Missouri 63110, USA

    Julie L. Prior & David Piwnica-Worms

  6. Laboratory for Optical and Computational Imaging, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA

    Kevin W. Eliceiri & Patricia J. Keely

Authors
  1. Kun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Callie A. Corsa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suzanne M. Ponik
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Julie L. Prior
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Piwnica-Worms
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kevin W. Eliceiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Patricia J. Keely
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gregory D. Longmore
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.Z., C.A.C., S.M.P. and J.L.P. were involved in project planning, experimental work and data analysis. D.P-W., K.W.E., P.J.K. and G.D.L. were involved in project planning and data analysis. G.D.L. wrote the manuscript. D.P-W. and P.J.K. provided editorial assistance in the writing of the manuscript.

Corresponding author

Correspondence to Gregory D. Longmore.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 4260 kb)

Supplementary Table 1

Supplementary Information (XLSX 12 kb)

Supplementary Table 2

Supplementary Information (XLSX 12 kb)

Supplementary Table 3

Supplementary Information (XLSX 26 kb)

Supplementary Table 41

Supplementary Information (XLSX 19 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, K., Corsa, C., Ponik, S. et al. The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis. Nat Cell Biol 15, 677–687 (2013). https://doi.org/10.1038/ncb2743

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb2743

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer