Benjamin Izar, Itay Tirosh, Elizabeth H. Stover, Isaac Wakiro, Michael S. Cuoco, Idan Alter, Christopher Rodman, Rachel Leeson, Mei-Ju Su, Parin Shah, Marcin Iwanicki, Sarah R. Walker, Abhay Kanodia, Johannes C. Melms, Shaolin Mei, Jia-Ren Lin, Caroline B. M. Porter, Michal Slyper, Julia Waldman, Livnat Jerby-Arnon, Orr Ashenberg, Titus J. Brinker, Caitlin Mills, Meri Rogava, Sébastien Vigneau, Peter K. Sorger, Levi A. Garraway, Panagiotis A. Konstantinopoulos, Joyce F. Liu, Ursula Matulonis, Bruce E. Johnson, Orit Rozenblatt-Rosen, Asaf Rotem, Aviv Regev
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 prognosis. 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 cells. 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 and provides a resource for the development of novel therapeutic approaches.