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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 cel... Full description

Journal Title: Nature medicine 2020-08, Vol.26 (8), p.1271-1279
Main Author: Izar, Benjamin
Other Authors: Tirosh, Itay , Stover, Elizabeth H , Wakiro, Isaac , Cuoco, Michael S , Alter, Idan , Rodman, Christopher , Leeson, Rachel , Su, Mei-Ju , Shah, Parin , Iwanicki, Marcin , Walker, Sarah R , Kanodia, Abhay , Melms, Johannes C , Mei, Shaolin , Lin, Jia-Ren , Porter, Caroline B M , Slyper, Michal , Waldman, Julia , Jerby-Arnon, Livnat , Ashenberg, Orr , Brinker, Titus J , Mills, Caitlin , Rogava, Meri , Vigneau, Sébastien , Sorger, Peter K , Garraway, Levi A , Konstantinopoulos, Panagiotis A , Liu, Joyce F , Matulonis, Ursula , Johnson, Bruce E , Rozenblatt-Rosen, Orit , Rotem, Asaf , Regev, Aviv
Format: Electronic Article Electronic Article
Language: English
Subjects:
RNA
Publisher: United States: Nature Publishing Group
ID: ISSN: 1078-8956
Link: https://www.ncbi.nlm.nih.gov/pubmed/32572264
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title: A single-cell landscape of high-grade serous ovarian cancer
format: Article
creator:
  • Izar, Benjamin
  • Tirosh, Itay
  • Stover, Elizabeth H
  • Wakiro, Isaac
  • Cuoco, Michael S
  • Alter, Idan
  • Rodman, Christopher
  • Leeson, Rachel
  • Su, Mei-Ju
  • Shah, Parin
  • Iwanicki, Marcin
  • Walker, Sarah R
  • Kanodia, Abhay
  • Melms, Johannes C
  • Mei, Shaolin
  • Lin, Jia-Ren
  • Porter, Caroline B M
  • Slyper, Michal
  • Waldman, Julia
  • Jerby-Arnon, Livnat
  • Ashenberg, Orr
  • Brinker, Titus J
  • Mills, Caitlin
  • Rogava, Meri
  • Vigneau, Sébastien
  • Sorger, Peter K
  • Garraway, Levi A
  • Konstantinopoulos, Panagiotis A
  • Liu, Joyce F
  • Matulonis, Ursula
  • Johnson, Bruce E
  • Rozenblatt-Rosen, Orit
  • Rotem, Asaf
  • Regev, Aviv
subjects:
  • Analysis
  • Anticancer properties
  • Antitumor agents
  • Ascites
  • Ascites - genetics
  • Ascites - pathology
  • Ascites cells
  • Cancer
  • Cell Line, Tumor
  • Copy number
  • Cystadenoma, Serous - genetics
  • Cystadenoma, Serous - pathology
  • Development and progression
  • DNA Copy Number Variations - genetics
  • Drug resistance
  • Drug Resistance, Neoplasm - genetics
  • Female
  • Fibroblasts
  • Fibroblasts - metabolism
  • Gene Expression Regulation, Neoplastic
  • Gene sequencing
  • Genetic aspects
  • Heterogeneity
  • Heterografts
  • Humans
  • Immunomodulation
  • Inflammation
  • Janus Kinase 1 - genetics
  • Macrophages
  • Mesenchyme
  • Neoplasm Grading
  • Neoplasm Proteins - genetics
  • Ovarian cancer
  • Ovarian carcinoma
  • Ovarian Neoplasms - genetics
  • Ovarian Neoplasms - pathology
  • Populations
  • Prognosis
  • Ribonucleic acid
  • RNA
  • RNA sequencing
  • Sequence Analysis, RNA
  • Signal Transduction - genetics
  • Single-Cell Analysis
  • STAT Transcription Factors - genetics
  • Transcriptomics
  • Tumors
  • Usage
  • Xenografts
  • Xenotransplantation
ispartof: Nature medicine, 2020-08, Vol.26 (8), p.1271-1279
description: 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.
language: eng
source:
identifier: ISSN: 1078-8956
fulltext: no_fulltext
issn:
  • 1078-8956
  • 1546-170X
url: Link


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titleA single-cell landscape of high-grade serous ovarian cancer
creatorIzar, Benjamin ; Tirosh, Itay ; Stover, Elizabeth H ; Wakiro, Isaac ; Cuoco, Michael S ; Alter, Idan ; Rodman, Christopher ; Leeson, Rachel ; Su, Mei-Ju ; Shah, Parin ; Iwanicki, Marcin ; Walker, Sarah R ; Kanodia, Abhay ; Melms, Johannes C ; Mei, Shaolin ; Lin, Jia-Ren ; Porter, Caroline B M ; Slyper, Michal ; Waldman, Julia ; Jerby-Arnon, Livnat ; Ashenberg, Orr ; Brinker, Titus J ; Mills, Caitlin ; Rogava, Meri ; Vigneau, Sébastien ; Sorger, Peter K ; Garraway, Levi A ; Konstantinopoulos, Panagiotis A ; Liu, Joyce F ; Matulonis, Ursula ; Johnson, Bruce E ; Rozenblatt-Rosen, Orit ; Rotem, Asaf ; Regev, Aviv
creatorcontribIzar, Benjamin ; Tirosh, Itay ; Stover, Elizabeth H ; Wakiro, Isaac ; Cuoco, Michael S ; Alter, Idan ; Rodman, Christopher ; Leeson, Rachel ; Su, Mei-Ju ; Shah, Parin ; Iwanicki, Marcin ; Walker, Sarah R ; Kanodia, Abhay ; Melms, Johannes C ; Mei, Shaolin ; Lin, Jia-Ren ; Porter, Caroline B M ; Slyper, Michal ; Waldman, Julia ; Jerby-Arnon, Livnat ; Ashenberg, Orr ; Brinker, Titus J ; Mills, Caitlin ; Rogava, Meri ; Vigneau, Sébastien ; Sorger, Peter K ; Garraway, Levi A ; Konstantinopoulos, Panagiotis A ; Liu, Joyce F ; Matulonis, Ursula ; Johnson, Bruce E ; Rozenblatt-Rosen, Orit ; Rotem, Asaf ; Regev, Aviv
descriptionMalignant 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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languageeng
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subjectAnalysis ; Anticancer properties ; Antitumor agents ; Ascites ; Ascites - genetics ; Ascites - pathology ; Ascites cells ; Cancer ; Cell Line, Tumor ; Copy number ; Cystadenoma, Serous - genetics ; Cystadenoma, Serous - pathology ; Development and progression ; DNA Copy Number Variations - genetics ; Drug resistance ; Drug Resistance, Neoplasm - genetics ; Female ; Fibroblasts ; Fibroblasts - metabolism ; Gene Expression Regulation, Neoplastic ; Gene sequencing ; Genetic aspects ; Heterogeneity ; Heterografts ; Humans ; Immunomodulation ; Inflammation ; Janus Kinase 1 - genetics ; Macrophages ; Mesenchyme ; Neoplasm Grading ; Neoplasm Proteins - genetics ; Ovarian cancer ; Ovarian carcinoma ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - pathology ; Populations ; Prognosis ; Ribonucleic acid ; RNA ; RNA sequencing ; Sequence Analysis, RNA ; Signal Transduction - genetics ; Single-Cell Analysis ; STAT Transcription Factors - genetics ; Transcriptomics ; Tumors ; Usage ; Xenografts ; Xenotransplantation
ispartofNature medicine, 2020-08, Vol.26 (8), p.1271-1279
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1Tirosh, Itay
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3Wakiro, Isaac
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12Kanodia, Abhay
13Melms, Johannes C
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21Brinker, Titus J
22Mills, Caitlin
23Rogava, Meri
24Vigneau, Sébastien
25Sorger, Peter K
26Garraway, Levi A
27Konstantinopoulos, Panagiotis A
28Liu, Joyce F
29Matulonis, Ursula
30Johnson, Bruce E
31Rozenblatt-Rosen, Orit
32Rotem, Asaf
33Regev, Aviv
title
0A single-cell landscape of high-grade serous ovarian cancer
1Nature medicine
addtitleNat Med
descriptionMalignant 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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0Analysis
1Anticancer properties
2Antitumor agents
3Ascites
4Ascites - genetics
5Ascites - pathology
6Ascites cells
7Cancer
8Cell Line, Tumor
9Copy number
10Cystadenoma, Serous - genetics
11Cystadenoma, Serous - pathology
12Development and progression
13DNA Copy Number Variations - genetics
14Drug resistance
15Drug Resistance, Neoplasm - genetics
16Female
17Fibroblasts
18Fibroblasts - metabolism
19Gene Expression Regulation, Neoplastic
20Gene sequencing
21Genetic aspects
22Heterogeneity
23Heterografts
24Humans
25Immunomodulation
26Inflammation
27Janus Kinase 1 - genetics
28Macrophages
29Mesenchyme
30Neoplasm Grading
31Neoplasm Proteins - genetics
32Ovarian cancer
33Ovarian carcinoma
34Ovarian Neoplasms - genetics
35Ovarian Neoplasms - pathology
36Populations
37Prognosis
38Ribonucleic acid
39RNA
40RNA sequencing
41Sequence Analysis, RNA
42Signal Transduction - genetics
43Single-Cell Analysis
44STAT Transcription Factors - genetics
45Transcriptomics
46Tumors
47Usage
48Xenografts
49Xenotransplantation
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19Jerby-Arnon, Livnat
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titleA single-cell landscape of high-grade serous ovarian cancer
authorIzar, Benjamin ; Tirosh, Itay ; Stover, Elizabeth H ; Wakiro, Isaac ; Cuoco, Michael S ; Alter, Idan ; Rodman, Christopher ; Leeson, Rachel ; Su, Mei-Ju ; Shah, Parin ; Iwanicki, Marcin ; Walker, Sarah R ; Kanodia, Abhay ; Melms, Johannes C ; Mei, Shaolin ; Lin, Jia-Ren ; Porter, Caroline B M ; Slyper, Michal ; Waldman, Julia ; Jerby-Arnon, Livnat ; Ashenberg, Orr ; Brinker, Titus J ; Mills, Caitlin ; Rogava, Meri ; Vigneau, Sébastien ; Sorger, Peter K ; Garraway, Levi A ; Konstantinopoulos, Panagiotis A ; Liu, Joyce F ; Matulonis, Ursula ; Johnson, Bruce E ; Rozenblatt-Rosen, Orit ; Rotem, Asaf ; Regev, Aviv
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0Analysis
1Anticancer properties
2Antitumor agents
3Ascites
4Ascites - genetics
5Ascites - pathology
6Ascites cells
7Cancer
8Cell Line, Tumor
9Copy number
10Cystadenoma, Serous - genetics
11Cystadenoma, Serous - pathology
12Development and progression
13DNA Copy Number Variations - genetics
14Drug resistance
15Drug Resistance, Neoplasm - genetics
16Female
17Fibroblasts
18Fibroblasts - metabolism
19Gene Expression Regulation, Neoplastic
20Gene sequencing
21Genetic aspects
22Heterogeneity
23Heterografts
24Humans
25Immunomodulation
26Inflammation
27Janus Kinase 1 - genetics
28Macrophages
29Mesenchyme
30Neoplasm Grading
31Neoplasm Proteins - genetics
32Ovarian cancer
33Ovarian carcinoma
34Ovarian Neoplasms - genetics
35Ovarian Neoplasms - pathology
36Populations
37Prognosis
38Ribonucleic acid
39RNA
40RNA sequencing
41Sequence Analysis, RNA
42Signal Transduction - genetics
43Single-Cell Analysis
44STAT Transcription Factors - genetics
45Transcriptomics
46Tumors
47Usage
48Xenografts
49Xenotransplantation
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1Tirosh, Itay
2Stover, Elizabeth H
3Wakiro, Isaac
4Cuoco, Michael S
5Alter, Idan
6Rodman, Christopher
7Leeson, Rachel
8Su, Mei-Ju
9Shah, Parin
10Iwanicki, Marcin
11Walker, Sarah R
12Kanodia, Abhay
13Melms, Johannes C
14Mei, Shaolin
15Lin, Jia-Ren
16Porter, Caroline B M
17Slyper, Michal
18Waldman, Julia
19Jerby-Arnon, Livnat
20Ashenberg, Orr
21Brinker, Titus J
22Mills, Caitlin
23Rogava, Meri
24Vigneau, Sébastien
25Sorger, Peter K
26Garraway, Levi A
27Konstantinopoulos, Panagiotis A
28Liu, Joyce F
29Matulonis, Ursula
30Johnson, Bruce E
31Rozenblatt-Rosen, Orit
32Rotem, Asaf
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2Stover, Elizabeth H
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4Cuoco, Michael S
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6Rodman, Christopher
7Leeson, Rachel
8Su, Mei-Ju
9Shah, Parin
10Iwanicki, Marcin
11Walker, Sarah R
12Kanodia, Abhay
13Melms, Johannes C
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15Lin, Jia-Ren
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26Garraway, Levi A
27Konstantinopoulos, Panagiotis A
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date2020-08
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0equal contribution
1AUTHOR CONTRIBUTIONS
2B.I., I.T., E.S., As.R. and Av.R. conceived and designed the overall study. E.S. P.A.S., J.L., U.M. provided samples, clinical annotation and reviewed clinical data. C.B.M.P., M.S., J.W., L.J-A., O.A., O.R-R. and As.R. coordinated data acquisition of HTAPP specimens. B.I., I.W., M.C., C.R., R.L., M.S., P.S., J.C.M., T.B., M.R., S.V. O.R-R., L.A.G., B.E.J. and As.R. coordinated and performed sample acquisition and processing. B.I., S.V., As.R. and O.R-R. oversaw sample processing. B.I., I.T., E.S., S.V., O.R-R. and As.R. oversaw sample sequencing. I.T., B.I., E.S. I.A. and Av.R. performed and interpreted computational analyses. B.I., E.S. and As.R. designed and oversaw in vitro experiments. B.I., I.W., R.L., M.I., S.W., C.M., J.C.M, and As.R. performed and analyzed in vitro experiments. B.I., S.M., P.K.S. and J.L. performed IF experiments. B.I., E.S. and As.R. oversaw in vivo experiments. B.I., I.T., E.S., As.R. and Av.R. interpreted the data. B.I., I.T., E.S., As.R. and Av.R. wrote the manuscript, and all authors reviewed and approved the final manuscript.
abstractMalignant 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.
copUnited States
pubNature Publishing Group
pmid32572264
doi10.1038/s41591-020-0926-0
tpages9
orcidid
0https://orcid.org/0000-0001-6313-3570
1https://orcid.org/0000-0003-2163-5120
2https://orcid.org/0000-0002-6578-3216
3https://orcid.org/0000-0001-5477-2987
4https://orcid.org/0000-0001-8375-8447
5https://orcid.org/0000-0002-2608-4084
6https://orcid.org/0000-0002-3364-1838
7https://orcid.org/0000-0002-5248-4823
8https://orcid.org/0000-0003-4702-7705
9https://orcid.org/0000-0002-1032-1479
10https://orcid.org/0000-0003-3293-3158
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