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.

中文翻译：

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铂诱导的 ITGA6 上调促进卵巢癌的化疗耐药和扩散。


铂（PT）耐药的上皮性卵巢癌（EOC）作为一种转移性疾病生长，在腹部和骨盆中播散。对于 PT 耐药性 EOC 患者来说，可选择的治疗方案非常少，并且对于 PT 耐药性的获得如何介导 EOC 扩散能力的增强知之甚少。在这里，利用同基因 PT 抗性细胞、遗传和药理学方法以及患者衍生模型，我们报告整合素 α6 (ITGA6) 在 PT 抗性细胞中过度表达，并且对于维持 EOC 转移能力和粘附依赖性 PT 抗性是必需的。使用体外方法，我们发现 PT 诱导正循环，通过刺激 ITGA6 转录和分泌，有助于形成转移前生态位，使 EOC 细胞能够扩散。在分子水平上，ITGA6 参与调节胰岛素样生长因子 (IGF) 的产生和可用性，过度刺激 IGF1R 通路并上调 Snail 表达。使用体内模型概括了体外数据，其中 ITGA6 的靶向可防止 PT 耐药性 EOC 传播并改善 PT 活性，支持 ITGA6 作为 EOC 患者有希望的药物靶点。