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A single-cell landscape of high-grade serous ovarian cancer
Authors
Idan Alter
Orr Ashenberg
+32 more
Titus J. Brinker
Michael S. Cuoco
Levi A. Garraway
Marcin Iwanicki
Benjamin Izar
Livnat Jerby-Arnon
Bruce E. Johnson
Abhay Kanodia
Panagiotis A. Konstantinopoulos
Rachel Leeson
Jia-Ren Lin
Joyce F. Liu
Ursula Matulonis
Shaolin Mei
Johannes C. Melms
Caitlin Mills
Caroline B. M. Porter
Aviv Regev
Christopher Rodman
Meri Rogava
Asaf Rotem
Orit Rozenblatt-Rosen
Parin Shah
Michal Slyper
Peter K. Sorger
Elizabeth H. Stover
Mei-Ju Su
Itay Tirosh
Sébastien Vigneau
Isaac Wakiro
Julia Waldman
Sarah R. Walker
Publication date
22 July 2021
Publisher
'Springer Science and Business Media LLC'
Doi
Cite
Abstract
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. 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
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Last time updated on 28/07/2022