TY - JOUR
T1 - TWIST1 induces expression of discoidin domain receptor 2 to promote ovarian cancer metastasis
AU - Grither, Whitney R.
AU - Divine, Laura M.
AU - Meller, Eric H.
AU - Wilke, Daniel J.
AU - Desai, Riva A.
AU - Loza, Andrew J.
AU - Zhao, Peinan
AU - Lohrey, Anne
AU - Longmore, Gregory D.
AU - Fuh, Katherine C.
N1 - Publisher Copyright:
© 2018 Macmillan Publishers Limited, part of Springer Nature.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85040640178&partnerID=8YFLogxK
U2 - 10.1038/s41388-017-0043-9
DO - 10.1038/s41388-017-0043-9
M3 - Article
C2 - 29348456
AN - SCOPUS:85040640178
SN - 0950-9232
VL - 37
SP - 1714
EP - 1729
JO - Oncogene
JF - Oncogene
IS - 13
ER -