Malignant abdominal fluid (ascites) frequently develops in women with advanced high-grade serous ovarian cancer (HGSOC) and is associated with drug resistance and a poor prognosis¹. To comprehensively characterize the HGSOC ascites ecosystem, we used single-cell RNA sequencing to profile ~11,000 cells from 22 ascites specimens from 11 patients with HGSOC. We found significant inter-patient variability in the composition and functional programs of ascites cells, including immunomodulatory fibroblast sub-populations and dichotomous macrophage populations. We found that the previously described immunoreactive and mesenchymal subtypes of HGSOC, which have prognostic implications, reflect the abundance of immune infiltrates and fibroblasts rather than distinct subsets of malignant cells². Malignant cell variability was partly explained by heterogeneous copy number alteration patterns or expression of a stemness program. Malignant cells shared expression of inflammatory programs that were largely recapitulated in single-cell RNA sequencing of ~35,000 cells from additionally collected samples, including three ascites, two primary HGSOC tumors and three patient ascites-derived xenograft models. Inhibition of the JAK/STAT pathway, which was expressed in both malignant cells and cancer-associated fibroblasts, had potent anti-tumor activity in primary short-term cultures and patient-derived xenograft models. Our work contributes to resolving the HSGOC landscape^3,4,5 and provides a resource for the development of novel therapeutic approaches.

患有晚期高级别浆液性卵巢癌 (HGSOC) 的女性经常出现恶性腹水（腹水），并且与耐药性和不良预后相关¹。为了全面表征 HGSOC 腹水生态系统，我们使用单细胞 RNA 测序对 11 名 HGSOC 患者的 22 份腹水样本中的约 11,000 个细胞进行了分析。我们发现腹水细胞的组成和功能程序存在显着的患者间差异，包括免疫调节成纤维细胞亚群和二分巨噬细胞群。我们发现，先前描述的 HGSOC 的免疫反应性和间充质亚型具有预后意义，反映了免疫浸润和成纤维细胞的丰度，而不是恶性细胞的不同亚型²。恶性细胞变异的部分原因是异质拷贝数改变模式或干性程序的表达。恶性肿瘤细胞共享炎症程序的表达，这些炎症程序在对额外收集的样本中约 35,000 个细胞的单细胞 RNA 测序中得到了重述，这些样本包括三个腹水、两个原发性 HGSOC 肿瘤和三个患者腹水衍生的异种移植模型。JAK/STAT 通路在恶性细胞和癌症相关成纤维细胞中表达，其抑制在原代短期培养物和患者来源的异种移植模型中具有有效的抗肿瘤活性。我们的工作有助于解决 HSGOC 问题^3、4、5，并为开发新型治疗方法提供资源。