A single-cell landscape of high-grade serous ovarian cancer.

Jun 25, 2020

Contributor: 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

A single-cell landscape of high-grade serous ovarian cancer.

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.

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About The Expert

Benjamin Izar

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA, USA.

Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Ludwig Center for Cancer Research at Harvard, Boston, MA, USA.

Laboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.

Columbia University Medical Center, Columbia Center for Translational Immunology, New York, NY, USA.

Itay Tirosh

Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

Elizabeth H Stover

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Isaac Wakiro

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Michael S Cuoco

Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Idan Alter

Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

Christopher Rodman

Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Rachel Leeson

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Mei-Ju Su

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Laboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.

Parin Shah

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Marcin Iwanicki

Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ, USA.

Sarah R Walker

Molecular, Cellular, and Biomedical Sciences, College of Life Sciences and Agriculture, University of New Hampshire, Durham, NH, USA.

Abhay Kanodia

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Johannes C Melms

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Shaolin Mei

Laboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.

Jia-Ren Lin

Laboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.

Caroline B M Porter

Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Michal Slyper

Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Julia Waldman

Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Livnat Jerby-Arnon

Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Orr Ashenberg

Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Titus J Brinker

German Cancer Research Center, Heidelberg, Germany.

Caitlin Mills

Laboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.

Meri Rogava

Laboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.

Sébastien Vigneau

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA, USA.

Peter K Sorger

Laboratory for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.

Levi A Garraway

Genentech, San Francisco, CA, USA.

Panagiotis A Konstantinopoulos

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Joyce F Liu

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Ursula Matulonis

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Bruce E Johnson

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA, USA.

Orit Rozenblatt-Rosen

Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Asaf Rotem

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA, USA.

Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Aviv Regev

Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. aregev@broadinstitute.org.

Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. aregev@broadinstitute.org.

Ludwig Center for Cancer Research at MIT, Boston, MA, USA. aregev@broadinstitute.org.

Howard Hughes Medical Institute, Chevy Chase, MD, USA. aregev@broadinstitute.org.

References

PubMed