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:

TWIST1 induces expression of discoidin domain receptor 2 to promote ovarian cancer metastasis

Oncogene volume 37, pages 1714–1729 (2018)Cite this article

Subjects

Abstract

The mesenchymal gene program has been shown to promote the metastatic progression of ovarian cancer; however, specific proteins induced by this program that lead to these metastatic behaviors have not been identified. Using patient derived tumor cells and established human ovarian tumor cell lines, we find that the Epithelial-to-Mesenchymal Transition inducing factor TWIST1 drives expression of discoidin domain receptor 2 (DDR2), a receptor tyrosine kinase (RTK) that recognizes fibrillar collagen as ligand. The expression and action of DDR2 was critical for mesothelial cell clearance, invasion and migration in ovarian tumor cells. It does so, in part, by upregulating expression and activity of matrix remodeling enzymes that lead to increased cleavage of fibronectin and spreading of tumor cells. Additionally, DDR2 stabilizes SNAIL1, allowing for sustained mesenchymal phenotype. In patient derived ovarian cancer specimens, DDR2 expression correlated with enhanced invasiveness. DDR2 expression was associated with advanced stage ovarian tumors and metastases. In vivo studies demonstrated that the presence of DDR2 is critical for ovarian cancer metastasis. These findings indicate that the collagen receptor DDR2 is critical for multiple steps of ovarian cancer progression to metastasis, and thus, identifies DDR2 as a potential new target for the treatment of metastatic ovarian cancer.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Yeung TL, Leung CS, Yip KP, Au Yeung CL, Wong ST, Mok SC. Cellular and molecular processes in ovarian cancer metastasis. A Review in the theme: cell and molecular processes in cancer metastasis. Am J Physiol Cell Physiol. 2015;309:C444–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Iwanicki MP, Davidowitz RA, Ng MR, Besser A, Muranen T, Merritt M, et al. Ovarian cancer spheroids use myosin-generated force to clear the mesothelium. Cancer Discov 2011;1:144–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cho A, Howell VM, Colvin EK. The extracellular matrix in epithelial ovarian cancer—a piece of a puzzle. Front Oncol 2015;5:245.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kenny HA, Kaur S, Coussens LM, Lengyel E. The initial steps of ovarian cancer cell metastasis are mediated by MMP-2 cleavage of vitronectin and fibronectin. J Clin Invest 2008;118:1367–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Davidowitz RA, Selfors LM, Iwanicki MP, Elias KM, Karst A, Piao H, et al. Mesenchymal gene program-expressing ovarian cancer spheroids exhibit enhanced mesothelial clearance. J Clin Invest. 2014;124:2611–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen D, Wang J, Zhang Y, Chen J, Yang C, Cao W, et al. Effect of down-regulated transcriptional repressor ZEB1 on the epithelial–mesenchymal transition of ovarian cancer cells.Int J Gynecol Cancer J Int Gynecol Cancer Soc2013;23:1357–66.

    Article  Google Scholar 

  7. Terauchi M, Kajiyama H, Yamashita M, Kato M, Tsukamoto H, Umezu T, et al. Possible involvement of TWIST in enhanced peritoneal metastasis of epithelial ovarian carcinoma. Clin Exp Metastas- 2007;24:329–39.

    Article  CAS  Google Scholar 

  8. Wang YL, Zhao XM, Shuai ZF, Li CY, Bai QY, Yu XW, et al. Snail promotes epithelial–mesenchymal transition and invasiveness in human ovarian cancer cells. Int J Clin Exp Med 2015;8:7388–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Bildsoe H, Fan X, Wilkie EE, Ashoti A, Jones VJ, Power M, et al. Transcriptional targets of TWIST1 in the cranial mesoderm regulate cell–matrix interactions and mesenchyme maintenance. Dev Biol 2016;418:189–203.

    Article  CAS  PubMed  Google Scholar 

  10. Chua HH, Yeh TH, Wang YP, Huang YT, Sheen TS, Lo YC, et al. Upregulation of discoidin domain receptor 2 in nasopharyngeal carcinoma. Head Neck 2008;30:427–36.

    Article  PubMed  Google Scholar 

  11. Corsa CA, Brenot A, Grither WR, Van Hove S, Loza AJ, Zhang K, et al. The action of discoidin domain receptor 2 in basal tumor cells and stromal cancer-associated fibroblasts is critical for breast cancer metastasis.Cell Rep2016;15:2510–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hammerman PSSM, Ramos AH, et al. Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancerkinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov. 2011;1:78–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ren T, Zhang W, Liu X, Zhao H, Zhang J, Zhang J, et al. Discoidin domain receptor 2 (DDR2) promotes breast cancer cell metastasis and the mechanism implicates epithelial–mesenchymal transition programme under hypoxia. J Pathol 2014;234:526–37.

    Article  CAS  PubMed  Google Scholar 

  14. Rodrigues R, Roque L, Espadinha C, Pinto A, Domingues R, Dinis J, et al. Comparative genomic hybridization, BRAF, RAS, RET, and oligo-array analysis in aneuploid papillary thyroid carcinomas. Oncol Rep 2007;18:917–26.

    CAS  PubMed  Google Scholar 

  15. Xie B, Lin W, Ye J, Wang X, Zhang B, Xiong S, et al. DDR2 facilitates hepatocellular carcinoma invasion and metastasis via activating ERK signaling and stabilizing SNAIL1. J Exp Clin Cancer Res 2015;34:101.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Xu J, Lu W, Zhang S, Zhu C, Ren T, Zhu T, et al. Overexpression of DDR2 contributes to cell invasion and migration in head and neck squamous cell carcinoma. Cancer Biol Ther 2014;15:612–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yan Z, Jin S, Wei Z, Huilian H, Zhanhai Y, Yue T, et al. Discoidin domain receptor 2 facilitates prostate cancer bone metastasis via regulating parathyroid hormone-related protein. Biochim Et Biophys Acta 2014;1842:1350–63.

    Article  CAS  Google Scholar 

  18. Zhang K, Corsa CA, Ponik SM, Prior JL, Piwnica-Worms D, Eliceiri KW, et al. The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis. Nat Cell Biol 2013;15:677–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shrivastava ARC, Campbell E, Kovac L, McGlynn M, Ryan TE, Davis S, Goldfarb MP, Glass DJ, Lemke G, Yancopoulos GD. An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors. Mol Cell. 1997;1:25–34.

    Article  CAS  PubMed  Google Scholar 

  20. Vogel W, Gish GD, Alves F, Pawson T. The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell 1997;1:13–23.

    Article  CAS  PubMed  Google Scholar 

  21. Nadiarnykh O, LaComb RB, Brewer MA, Campagnola PJ. Alterations of the extracellular matrix in ovarian cancer studied by second harmonic generation imaging microscopy. BMC Cancer 2010;10:94.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Borza CM, Pozzi A. Discoidin domain receptors in disease. Matrix biology. J Int Soc Matrix Biol 2014;34:185–92.

    Article  CAS  Google Scholar 

  23. Valiathan RR, Marco M, Leitinger B, Kleer CG, Fridman R. Discoidin domain receptor tyrosine kinases: new players in cancer progression. Cancer Metastas- Rev 2012;31:295–321.

    Article  CAS  Google Scholar 

  24. Leitinger B. Discoidin domain receptor functions in physiological and pathological conditions. Int Rev Cell Mol Biol 2014;310:39–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Xu DB H, Chang F, Huang PH, Farndale RW, Leitinger B, Discoidin domain receptors promote a1b1- and a2b1-integrin mediated cell adhesion to collagen by enhancing integrin activation. PLoS ONE. 2012;7:e52209

    Article  Google Scholar 

  26. Davidson B, Trope CG, Reich R. Epithelial–mesenchymal transition in ovarian carcinoma. Front Oncol. 2012;2:33.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Xu J, Lamouille S, Derynck R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res 2009;19:156–72.

    Article  CAS  PubMed  Google Scholar 

  28. Davidowitz RA, Iwanicki MP, Brugge JS. In vitro mesothelial clearance assay that models the early steps of ovarian cancer metastasis. JoVE. 2012;60:pii:3888.

  29. Elias MC, Tozer KR, Silber JR, Mikheeva S, Deng M, Morrison RS, et al. TWIST is expressed in human gliomas and promotes invasion. Neoplasia. 2005;7:824–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Matsuo N, Shiraha H, Fujikawa T, Takaoka N, Ueda N, Tanaka S, et al. Twist expression promotes migration and invasion in hepatocellular carcinoma. BMC Cancer 2009;9:240.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Wang Y, Liu J, Ying X, Lin PC, Zhou BP, Twist-mediated epithelial–mesenchymal transition promotes breast tumor cell invasion via inhibition of hippo pathway. Sci Rep2016;6:24606

    Article  PubMed  PubMed Central  Google Scholar 

  32. Yang Z, Zhang X, Gang H, Li X, Li Z, Wang T, et al. Up-regulation of gastric cancer cell invasion by Twist is accompanied by N-cadherin and fibronectin expression. Biochem Biophys Res Commun 2007;358:925–30.

    Article  CAS  PubMed  Google Scholar 

  33. Son H, Moon A. Epithelial–mesenchymal transition and cell invasion. Toxicol Res 2010;26:245–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002;2:161–74.

    Article  CAS  PubMed  Google Scholar 

  35. Olaso E, Ikeda K, Eng FJ, Xu L, Wang LH, Lin HC, et al. DDR2 receptor promotes MMP-2-mediated proliferation and invasion by hepatic stellate cells. J Clin Invest. 2001;108:1369–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Olaso E, Labrador JP, Wang L, Ikeda K, Eng FJ, Klein R, et al. Discoidin domain receptor 2 regulates fibroblast proliferation and migration through the extracellular matrix in association with transcriptional activation of matrix metalloproteinase-2. J Biol Chem. 2002;277:3606–13.

    Article  CAS  PubMed  Google Scholar 

  37. Xu L, Peng H, Wu D, Hu K, Goldring MB, Olsen BR, et al. Activation of the discoidin domain receptor 2 induces expression of matrix metalloproteinase 13 associated with osteoarthritis in mice. J Biol Chem 2005;280:548–55.

    Article  CAS  PubMed  Google Scholar 

  38. Majkowska I, Shitomi Y, Ito N, Gray NS, Itoh Y. Discoidin domain receptor 2 mediates collagen-induced activation of membrane-type 1 matrix metalloproteinase in human fibroblasts. J Biol Chem 2017;292:6633–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang X, Chen CT, Bhargava M, Torzilli PA, A comparative study of fibronectin cleavage by MMP-1, -3, -13, and -14. Cartilage 2012;3:267–77.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Tothill RW, Tinker AV, George J, Brown R, Fox SB, Lade S, et al. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin Cancer Res J Am Assoc Cancer Res 2008;14:5198–208.

    Article  CAS  Google Scholar 

  41. Fan Y, Xu Z, Fan J, Huang L, Ye M, Shi K, et al. Prognostic significance of discoidin domain receptor 2 (DDR2) expression in ovarian cancer. Am J Transl Res. 2016;8:2845–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Rauch J, Volinsky N, Romano D, Kolch W. The secret life of kinases: functions beyond catalysis. Cell Commun Signal Ccs 2011;9:23.

    Article  CAS  PubMed  Google Scholar 

  43. Pankov R, Yamada KM. Fibronectin at a glance. J Cell Sci. 2002;115:3861–3.

    Article  CAS  PubMed  Google Scholar 

  44. Pradeep S, Kim SW, Wu SY, Nishimura M, Chaluvally-Raghavan P, Miyake T, et al. Hematogenous metastasis of ovarian cancer: rethinking mode of spread. Cancer Cell 2014;26:77–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Burleson KM, Boente MP, Pambuccian SE, Skubitz AP. Disaggregation and invasion of ovarian carcinoma ascites spheroids. J Transl Med. 2006;4:6.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Domcke S, Sinha R, Levine DA, Sander C, Schultz N. Evaluating cell lines as tumour models by comparison of genomic profiles. Nat Commun 2013;4:2126.

    Article  PubMed  Google Scholar 

  47. Coelho NM, Arora PD, van Putten S, Boo S, Petrovic P, Lin AX, et al. Discoidin domain receptor 1 mediates myosin-dependent collagen contraction. Cell Rep 2017;18:1774–90.

    Article  CAS  PubMed  Google Scholar 

  48. Kenny HA, Dogan S, Zillhardt M, Mitra AK, Yamada SD, Krausz T, et al. Organotypic models of metastasis: a three-dimensional culture mimicking the human peritoneum and omentum for the study of the early steps of ovarian cancer metastasis. Cancer Treat Res 2009;149:335–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Yeh JE, Toniolo PA, Frank DA. Targeting transcription factors: promising new strategies for cancer therapy. Curr Opin Oncol 2013;25:652–8.

    Article  CAS  PubMed  Google Scholar 

  50. Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood. 2000;96:925–32.

    CAS  PubMed  Google Scholar 

  51. Livak KJ, Schmittgen TD, Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–8.

    Article  CAS  PubMed  Google Scholar 

  52. Zhang K, Grither WR, Van Hove S, Biswas H, Ponik SM, Eliceiri KW, et al. Mechanical signals regulate and activate SNAIL1 protein to control the fibrogenic response of cancer-associated fibroblasts. J Cell Sci. 2016;129:1989–2002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

Funding

2K12HD000849–28 (KCF); NIHCA196205 (GDL); Cancer Frontier Fund 8002-88 (KCF and GDL).

Author information

Author notes

  1. Whitney R. Grither, Laura M. Divine, Gregory D. Longmore, and Katherine C. Fuh contributed equally to this work.

Authors and Affiliations

  1. ICCE Institute, Washington University, St. Louis, MO, USA

    Whitney R. Grither, Andrew J. Loza, Anne Lohrey & Gregory D. Longmore

  2. Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, USA

    Laura M. Divine, Eric H. Meller, Daniel J. Wilke, Riva A. Desai & Katherine C. Fuh

  3. Center for Reproductive Health Sciences (CRepHS), Washington University, St. Louis, USA

    Eric H. Meller, Daniel J. Wilke, Riva A. Desai, Anne Lohrey & Katherine C. Fuh

  4. Division of Clinical Research, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, USA

    Peinan Zhao

Authors
  1. Whitney R. Grither
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura M. Divine
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eric H. Meller
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniel J. Wilke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Riva A. Desai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrew J. Loza
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peinan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anne Lohrey
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gregory D. Longmore
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Katherine C. Fuh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Katherine C. Fuh.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Grither, W.R., Divine, L.M., Meller, E.H. et al. TWIST1 induces expression of discoidin domain receptor 2 to promote ovarian cancer metastasis. Oncogene 37, 1714–1729 (2018). https://doi.org/10.1038/s41388-017-0043-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-017-0043-9

This article is cited by

Search

Advanced search

Quick links