Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University, St. Louis, Missouri.
Center for Reproductive Health Sciences, Division of Biology and Biomedical Sciences, Washington University, St. Louis, Missouri.
Mol Cancer Res. 2023 Nov 1;21(11):1234-1248. doi: 10.1158/1541-7786.MCR-23-0347.
Ovarian cancer is the leading cause of gynecologic cancer-related deaths. The propensity for metastasis within the peritoneal cavity is a driving factor for the poor outcomes associated with this disease, but there is currently no effective therapy targeting metastasis. In this study, we investigate the contribution of stromal cells to ovarian cancer metastasis and identify normal stromal cell expression of the collagen receptor, discoidin domain receptor 2 (DDR2), that acts to facilitate ovarian cancer metastasis. In vivo, global genetic inactivation of Ddr2 impairs the ability of Ddr2-expressing syngeneic ovarian cancer cells to spread throughout the peritoneal cavity. Specifically, DDR2 expression in mesothelial cells lining the peritoneal cavity facilitates tumor cell attachment and clearance. Subsequently, omentum fibroblast expression of DDR2 promotes tumor cell invasion. Mechanistically, we find DDR2-expressing fibroblasts are more energetically active, such that DDR2 regulates glycolysis through AKT/SNAI1 leading to suppressed fructose-1,6-bisphosphatase and increased hexokinase activity, a key glycolytic enzyme. Upon inhibition of DDR2, we find decreased protein synthesis and secretion. Consequently, when DDR2 is inhibited, there is reduction in secreted extracellular matrix proteins important for metastasis. Specifically, we find that fibroblast DDR2 inhibition leads to decreased secretion of the collagen crosslinker, LOXL2. Adding back LOXL2 to DDR2 deficient fibroblasts rescues the ability of tumor cells to invade. Overall, our results suggest that stromal cell expression of DDR2 is an important mediator of ovarian cancer metastasis.
DDR2 is highly expressed by stromal cells in ovarian cancer that can mediate metastasis and is a potential therapeutic target in ovarian cancer.
卵巢癌是妇科癌症相关死亡的主要原因。在腹腔内转移的倾向是与这种疾病相关的不良预后的一个驱动因素，但目前没有针对转移的有效治疗方法。在这项研究中，我们研究了基质细胞对卵巢癌转移的贡献，并确定了正常基质细胞表达胶原受体 discoidin domain receptor 2 (DDR2)，它有助于卵巢癌转移。在体内，DDR2 的全局基因失活会损害表达 DDR2 的同源卵巢癌细胞在整个腹腔内扩散的能力。具体而言，腹膜腔衬里间皮细胞中的 DDR2 表达促进了肿瘤细胞的附着和清除。随后，网膜成纤维细胞中 DDR2 的表达促进了肿瘤细胞的侵袭。从机制上讲，我们发现 DDR2 表达的成纤维细胞更具活力，因此 DDR2 通过 AKT/SNAI1 调节糖酵解，导致果糖-1,6-二磷酸酶抑制和己糖激酶活性增加，这是一种关键的糖酵解酶。抑制 DDR2 后，我们发现蛋白质合成和分泌减少。因此，当抑制 DDR2 时，与转移相关的重要细胞外基质蛋白的分泌减少。具体来说，我们发现成纤维细胞 DDR2 抑制会导致胶原交联酶 LOXL2 的分泌减少。向 DDR2 缺陷成纤维细胞中添加 LOXL2 可恢复肿瘤细胞侵袭的能力。总体而言，我们的结果表明，卵巢癌中基质细胞表达的 DDR2 是卵巢癌转移的重要介质。
DDR2 在卵巢癌中的基质细胞中高度表达，可介导转移，是卵巢癌的潜在治疗靶点。
