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

Oncogenevolume 37pages17141729 (2018) | Download Citation

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.

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Author notes

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

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

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Funding

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

Conflict of interest

The authors declare that they have no competing interests.

Corresponding author

Correspondence to Katherine C. Fuh.

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