1. A single-cell landscape of high-grade serous ovarian cancer
- Author
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Bruce E. Johnson, Rachel Leeson, Joyce F. Liu, Benjamin Izar, Sébastien Vigneau, Parin Shah, Christopher Rodman, Mei-Ju Su, Aviv Regev, Marcin P. Iwanicki, Levi A. Garraway, Sarah R. Walker, Asaf Rotem, Livnat Jerby-Arnon, Michal Slyper, Isaac Wakiro, Caroline B. M. Porter, Orit Rozenblatt-Rosen, Itay Tirosh, Caitlin E. Mills, Abhay Kanodia, Shaolin Mei, Ursula A. Matulonis, Julia Waldman, Titus J. Brinker, Peter K. Sorger, Michael S. Cuoco, Johannes C. Melms, Elizabeth H. Stover, Idan Alter, Orr Ashenberg, Jia-Ren Lin, Meri Rogava, and Panagiotis A. Konstantinopoulos
- Subjects
0301 basic medicine ,DNA Copy Number Variations ,Cell ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Single-cell analysis ,Cell Line, Tumor ,Ascites ,medicine ,Humans ,Regulation of gene expression ,Ovarian Neoplasms ,Sequence Analysis, RNA ,Mesenchymal stem cell ,Cystadenoma, Serous ,JAK-STAT signaling pathway ,General Medicine ,Janus Kinase 1 ,Fibroblasts ,Prognosis ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,STAT Transcription Factors ,030104 developmental biology ,medicine.anatomical_structure ,Cell culture ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Heterografts ,Female ,medicine.symptom ,Neoplasm Grading ,Single-Cell Analysis ,Signal Transduction - Abstract
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 landscape3-5 and provides a resource for the development of novel therapeutic approaches.
- Published
- 2020