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

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. •The projection of FTE subtypes refines the molecular classification of SOC•Comprehensive single-cell profiling of FTE cells identifies six molecular subtypes•Substantial non-genetic heterogeneity of HGSOC identified in 1,700 tumors•A mesenchymal-high HGSOC subtype is robustly correlated with poor prognosis Using single-cell RNA sequencing, Hu et al. identify six subtypes of fallopian tube epithelium (FTE) cells in normal human fallopian tube tissues. The FTE cellular subtypes reveal intra-tumoral heterogeneity in serous ovarian cancer (SOC) and define SOC subtypes that correlate with patient prognosis.