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

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 landscape^3-5 and provides a resource for the development of novel therapeutic approaches.

SUBMITTER: Izar B

PROVIDER: S-EPMC7723336 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Izar Benjamin B Tirosh Itay I Stover Elizabeth H EH Wakiro Isaac I Cuoco Michael S MS Alter Idan I Rodman Christopher C Leeson Rachel R Su Mei-Ju MJ Shah Parin P Iwanicki Marcin M Walker Sarah R SR Kanodia Abhay A Melms Johannes C JC Mei Shaolin S Lin Jia-Ren JR Porter Caroline B M CBM Slyper Michal M Waldman Julia J Jerby-Arnon Livnat L Ashenberg Orr O Brinker Titus J TJ Mills Caitlin C Rogava Meri M Vigneau Sébastien S Sorger Peter K PK Garraway Levi A LA Konstantinopoulos Panagiotis A PA Liu Joyce F JF Matulonis Ursula U Johnson Bruce E BE Rozenblatt-Rosen Orit O Rotem Asaf A Regev Aviv A

Nature medicine 20200622 8

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<sup>1</sup>. 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 immunomodulat ...[more]

PMID: 32572264

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Project description:BACKGROUND:Poly (ADP-ribose) polymerase inhibitors targeting BRCA1/2 mutations are available for treating patients with high-grade serous ovarian cancer. These treatments may be more appropriately directed to patients who might respond if the tumor tissue is additionally tested by next-generation sequencing with a multi-gene panel and Sanger sequencing of a blood sample. In this study, we compared the results obtained using the next-generation sequencing multi-gene panel to a known germline BRCA1/2 mutational state determined by conventional Sanger sequencing to evaluate the landscape of somatic mutations in high-grade serous ovarian cancer tumors. METHODS:Cancer tissue from 98 patients with high-grade serous ovarian cancer who underwent Sanger sequencing for germline BRCA1/2 analysis were consecutively analyzed for somatic mutations using a next-generation sequencing 170-gene panel. RESULTS:Twenty-four patients (24.5%) showed overall BRCA1/2 mutations. Seven patients (7.1%) contained only somatic BRCA1/2 mutations with wild-type germline BRCA1/2, indicating acquired mutation of BRCA1/2. Three patients (3.1%) showed reversion of germline BRCA1 mutations. Among the 14 patients (14.3%) with both germline and somatic mutations in BRCA1/2, two patients showed different variations of BRCA1/2 mutations. The next-generation sequencing panel test for somatic mutation detected other pathogenic variations including RAD51D and ARID1A, which are possible targets of poly (ADP-ribose) polymerase inhibitors. Compared to conventional Sanger sequencing alone, next-generation sequencing-based tissue analysis increased the number of candidates for poly (ADP-ribose) polymerase inhibitor treatment from 17.3% (17/98) to 26.5% (26/98). CONCLUSIONS:Somatic mutation analysis by next-generation sequencing, in addition to germline BRCA1/2 mutation analysis, should become the standard of care for managing women with high-grade serous ovarian cancer to widen the indication of poly (ADP-ribose) polymerase inhibitors.

Dataset Information

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

Publications

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

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