Peritoneal dissemination of ovarian cancer (OvCa) arises from the surface of the peritoneum, covered by monolayer of mesothelial cells (MCs). Given that both OvCa cells and MCs are present in the same peritoneal metastatic microenvironment, they may establish cell-to-cell crosstalk or phenotypic alterations including the acquisition of platinum-resistance in OvCa cells. Herein, we report how OvCa-associated mesothelial cells (OCAMs) induce platinum-resistance in OvCa cells through direct cell-to-cell crosstalk. We evaluated mutual associations between OvCa cells and human primary MCs with in vitro coculturing experimental models and in silico omics data analysis. The role of OCAMs was also investigated using clinical samples and in vivo mice models. Results of in vitro experiments show that mesenchymal transition is induced in OCAMs primarily by TGF-β1 stimulation. Furthermore, OCAMs influence the behavior of OvCa cells as a component of the tumor microenvironment of peritoneal metastasis. Mechanistically, OCAMs can induce decreased platinum-sensitivity in OvCa cells via induction of the FN1/Akt signaling pathway via cell-to-cell interactions. Histological analysis of OvCa peritoneal metastasis also illustrated FN1 expression in stromal cells that are supposed to originate from MCs. Further, we also confirmed the activation of Akt signaling in OvCa cells in contact with TGF-β1 stimulated peritoneum, using an in vivo mice model. Our results suggest that the tumor microenvironment, enhanced by direct cell-to-cell crosstalk between OvCa cells and OCAMs, induces acquisition of platinum-resistance in OvCa cells, which may serve as a novel therapeutic target for prevention of OvCa peritoneal dissemination.

中文翻译：

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卵巢癌相关间皮细胞通过FN1 / Akt信号通路在腹膜转移中诱导获得性铂耐药。

卵巢癌（OvCa）的腹膜扩散来自腹膜表面，被间皮细胞（MCs）单层覆盖。鉴于OvCa细胞和MC都存在于相同的腹膜转移微环境中，它们可能会建立细胞间串扰或表型改变，包括在OvCa细胞中获得铂耐药性。本文中，我们报道了OvCa相关间皮细胞（OCAM）如何通过直接的细胞间串扰在OvCa细胞中诱导铂耐药性。我们通过体外共培养实验模型和计算机组学数据分析评估了OvCa细胞与人原代MC之间的相互关联。还使用临床样品和体内小鼠模型研究了OCAM的作用。体外实验结果表明，主要通过TGF-β1刺激在OCAM中诱导间质转化。此外，OCAM影响作为腹膜转移肿瘤微环境的一部分的OvCa细胞的行为。从机理上讲，OCAM可以通过细胞间相互作用诱导FN1 / Akt信号传导途径，诱导OvCa细胞的铂敏感性降低。OvCa腹膜转移的组织学分析也说明了FN1在基质细胞中的表达，该基质细胞可能起源于MC。此外，我们还使用体内小鼠模型证实了与TGF-β1刺激的腹膜接触的OvCa细胞中Akt信号的激活。我们的研究结果表明，OvCa细胞与OCAM之间的直接细胞间串扰增强了肿瘤的微​​环境，