单细胞测序正常输卵管上皮细胞揭示浆液性卵巢癌非遗传异质性的 repertoire。

The Repertoire of Serous Ovarian Cancer Non-genetic Heterogeneity Revealed by Single-Cell Sequencing of Normal Fallopian Tube Epithelial Cells.

机构信息

Ovarian Cancer Cell Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford OX3 9DU, UK; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.

Ovarian Cancer Cell Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Nuffield Department of Women's & Reproductive Health, University of Oxford, Oxford OX3 9DU, UK; Gene Regulatory Networks in Development and Disease Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.

出版信息

Cancer Cell. 2020 Feb 10;37(2):226-242.e7. doi: 10.1016/j.ccell.2020.01.003.

DOI:10.1016/j.ccell.2020.01.003

PMID:32049047

Abstract

The inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH in serous ovarian cancer (SOC) can be accurately measured when informed by the molecular signatures of the normal fallopian tube epithelium (FTE) cells, the cells of origin of SOC. Surveying the transcriptomes of ∼6,000 FTE cells, predominantly from non-ovarian cancer patients, identified 6 FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH. Importantly, NGH-based stratification of ∼1,700 tumors robustly correlated with survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC.

摘要

细胞状态的互分化促进了癌细胞在压力下的存活，并促进了非遗传异质性（NGH）。因此，NGH 是肿瘤弹性的替代指标，但由于遗传异质性使其定量变得复杂。在这里，我们表明，当 SOC 中 SOC 起源细胞的正常输卵管上皮（FTE）细胞的分子特征提供信息时，可以准确测量浆液性卵巢癌（SOC）中的 NGH。调查了约 6000 个 FTE 细胞的转录组，这些细胞主要来自非卵巢癌患者，鉴定了 6 个 FTE 亚型。我们使用亚型特征来推断 SOC 的表达数据，发现了大量的肿瘤内 NGH。重要的是，基于 NGH 的约 1700 个肿瘤的分层与生存情况密切相关。我们的研究结果为 SOC 的准确预后和治疗分层奠定了基础。