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.

中文翻译：

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TWIST1诱导盘状蛋白结构域受体2的表达，以促进卵巢癌转移。

间充质基因程序已被证明可以促进卵巢癌的转移进程。但是，尚未确定该程序诱导的导致这些转移行为的特定蛋白质。使用患者衍生的肿瘤细胞和已建立的人卵巢肿瘤细胞系，我们发现上皮到间充质转化诱导因子TWIST1驱动盘状蛋白结构域受体2（DDR2）的表达，盘状蛋白结构域受体2（DDR2）是一种受体酪氨酸激酶（RTK），可识别纤维状胶原作为配体。 。DDR2的表达和作用对于卵巢肿瘤细胞间皮细胞清除，侵袭和迁移至关重要。这样做部分是通过上调基质重塑酶的表达和活性，从而导致纤连蛋白的裂解增加和肿瘤细胞扩散。此外，DDR2可以稳定SNAIL1，允许持续的间充质表型。在患者来源的卵巢癌标本中，DDR2表达与侵袭性增强相关。DDR2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对于卵巢癌发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。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对于卵巢癌发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。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对于卵巢癌发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。