Serous ovarian carcinoma is the most frequent histological subgroup of ovarian cancer and the leading cause of death among gynecologic tumors. The tumor microenvironment and cancer-associated fibroblasts (CAFs) have a critical role in the origin and progression of cancer. We comprehensively characterized the crosstalk between CAFs and ovarian cancer cells from malignant fluids to identify specific ligands and receptors mediating intercellular communications and disrupted pathways related to prognosis and therapy response. Malignant fluids of serous ovarian cancer, including tumor-derived organoids, CAFs-enriched (eCAFs), and malignant effusion cells (no cultured) paired with normal ovarian tissues, were explored by RNA-sequencing. These data were integrated with single-cell RNA-sequencing data of ascites from ovarian cancer patients. The most relevant ligand and receptor interactions were used to identify differentially expressed genes with prognostic values in ovarian cancer. CAF ligands and epithelial cancer cell receptors were enriched for PI3K-AKT, focal adhesion, and epithelial-mesenchymal transition signaling pathways. Collagens, MIF, MDK, APP, and laminin were detected as the most significant signaling, and the top ligand-receptor interactions THBS2/THBS3 (CAFs)—CD47 (cancer cells), MDK (CAFs)—NCL/SDC2/SDC4 (cancer cells) as potential therapeutic targets. Interestingly, 34 genes encoding receptors and ligands of the PI3K pathway were associated with the outcome, response to treatment, and overall survival in ovarian cancer. Up-regulated genes from this list consistently predicted a worse overall survival (hazard ratio > 1.0 and log-rank P < 0.05) in two independent validation cohorts. This study describes critical signaling pathways, ligands, and receptors involved in the communication between CAFs and cancer cells that have prognostic and therapeutic significance in ovarian cancer.

中文翻译：

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单细胞和大量 RNA 测序揭示了与浆液性卵巢癌总体存活率较差相关的配体和受体

浆液性卵巢癌是卵巢癌最常见的组织学亚组，也是妇科肿瘤中死亡的主要原因。肿瘤微环境和癌症相关成纤维细胞 (CAF) 在癌症的起源和进展中起着关键作用。我们全面表征了 CAF 和来自恶性液体的卵巢癌细胞之间的串扰，以确定介导细胞间通讯和与预后和治疗反应相关的中断通路的特定配体和受体。通过 RNA 测序探索浆液性卵巢癌的恶性液体，包括肿瘤来源的类器官、富含 CAFs (eCAFs) 和与正常卵巢组织配对的恶性渗出细胞（未培养）。这些数据与卵巢癌患者腹水的单细胞 RNA 测序数据相结合。最相关的配体和受体相互作用用于鉴定在卵巢癌中具有预后价值的差异表达基因。CAF 配体和上皮癌细胞受体因 PI3K-AKT、粘着斑和上皮-间质转化信号通路而富集。胶原蛋白、MIF、MDK、APP 和层粘连蛋白被检测为最重要的信号，以及最重要的配体-受体相互作用 THBS2/THBS3 (CAFs)-CD47（癌细胞）、MDK (CAFs)-NCL/SDC2/SDC4（癌症细胞）作为潜在的治疗靶点。有趣的是，编码 PI3K 通路受体和配体的 34 个基因与卵巢癌的结果、治疗反应和总生存期相关。此列表中的上调基因一致预测更差的总体生存率（风险比 > 1.0 和对数秩 P < 0. 05) 在两个独立的验证队列中。本研究描述了参与 CAF 和癌细胞之间通讯的关键信号通路、配体和受体，它们对卵巢癌具有预后和治疗意义。