ICCE Institute, Washington University, St. Louis, MO, USA.
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, USA.
Oncogene. 2018 Mar;37(13):1714-1729. doi: 10.1038/s41388-017-0043-9. Epub 2018 Jan 19.
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.
间质基因程序已被证明可促进卵巢癌的转移进展；然而，该程序诱导的导致这些转移行为的特定蛋白质尚未被鉴定。使用患者来源的肿瘤细胞和已建立的人卵巢肿瘤细胞系，我们发现上皮-间质转化诱导因子 TWIST1 驱动 discoidin 结构域受体 2（DDR2）的表达，DDR2 是一种受体酪氨酸激酶（RTK），可识别纤维胶原作为配体。DDR2 的表达和作用对于卵巢肿瘤细胞中间皮细胞的清除、侵袭和迁移至关重要。它通过上调基质重塑酶的表达和活性来部分实现这一点，这导致纤连蛋白的切割增加和肿瘤细胞的扩展。此外，DDR2 稳定 SNAIL1，从而允许持续的间充质表型。在患者来源的卵巢癌标本中，DDR2 的表达与侵袭性增强相关。DDR2 的表达与晚期卵巢肿瘤和转移有关。体内研究表明，DDR2 的存在对于卵巢癌转移至关重要。这些发现表明，胶原受体 DDR2 对于卵巢癌进展为转移的多个步骤至关重要，因此，将 DDR2 鉴定为治疗转移性卵巢癌的潜在新靶标。
