PDF(Pubmed)
Abstract：
Platinum (PT)-resistant Epithelial Ovarian Cancer (EOC) grows as a metastatic disease, disseminating in the abdomen and pelvis. Very few options are available for PT-resistant EOC patients, and little is known about how the acquisition of PT-resistance mediates the increased spreading capabilities of EOC. Here, using isogenic PT-resistant cells, genetic and pharmacological approaches, and patient-derived models, we report that Integrin α6 (ITGA6) is overexpressed by PT-resistant cells and is necessary to sustain EOC metastatic ability and adhesion-dependent PT-resistance. Using in vitro approaches, we showed that PT induces a positive loop that, by stimulating ITGA6 transcription and secretion, contributes to the formation of a pre-metastatic niche enabling EOC cells to disseminate. At molecular level, ITGA6 engagement regulates the production and availability of insulin-like growth factors (IGFs), over-stimulating the IGF1R pathway and upregulating Snail expression. In vitro data were recapitulated using in vivo models in which the targeting of ITGA6 prevents PT-resistant EOC dissemination and improves PT-activity, supporting ITGA6 as a promising druggable target for EOC patients.
摘要：
铂（PT）耐药上皮性卵巢癌（EOC）作为一种转移性疾病，散布在腹部和骨盆。对PT耐药的EOC患者几乎没有选择，对PT抗性的获得如何介导EOC的传播能力的增加知之甚少。这里,使用等基因PT抗性细胞，遗传和药理学方法，和病人衍生的模型，我们报道，整合素α6（ITGA6）被PT抗性细胞过表达，并且是维持EOC转移能力和粘附依赖性PT抗性所必需的。使用体外方法，我们发现PT诱导了一个正循环，通过刺激ITGA6转录和分泌，有助于形成转移前的生态位，使EOC细胞能够传播。在分子水平上,ITGA6参与调节胰岛素样生长因子（IGFs）的生产和可用性，过度刺激IGF1R途径并上调Snail表达。使用体内模型概述了体外数据，其中ITGA6的靶向可防止PT抗性EOC传播并改善PT活性，支持ITGA6作为EOC患者的有希望的药物靶标。
