The repertoire of serous ovarian cancer non-genetic heterogeneity revealed by single-cell sequencing of normal fallopian tube epithelial cells

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 can be accurately measured when informed by the molecular signatures of the normal cells of origin.We surveyed the transcriptomes of ~ 4000 normal fallopian tube epithelial (FTE) cells, the cells of origin of serous ovarian cancer (SOC), and identified six FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH that was previously unrecognized. Importantly, NGH-based stratification of ~1700 tumors robustly predicted survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC. Highlights 1. The projection of FTE subtypes refines the molecular classification of serous OC 2. Comprehensive single-cell profiling of FTE cells identifies 6 molecular subtypes 3. Substantial non-genetic heterogeneity of HGSOC identified in 1700 tumors 4. A mesenchymal-high HGSOC subtype is robustly correlated with poor prognosis

IGF2BP1 is a targetable SRC/MAPK-dependent driver of invasive growth in ovarian cancer

“…1E and Supplementary Fig. 1G) and functional studies suggest a putative connection to the secretory cell signatures 'Cell Cycle' and 'EMT' [14]. Moreover, IGF2BP1 was recently shown to modulate the cell cycle in an E2F1-dependent manner [32].…”

“…EMT, characterized by the loss of CDH1 (E-cadherin) positive cell-cell contacts termed adherens junctions (AJs), is thought to underly progression of the mesenchymal-like subtype. Recent single-cell sequencing and bulk sequencing deconvolution analyses identified cellular HGSOC subtypes on the basis of non-genetic heterogeneity, demonstrating that HGSOC tumours with a high proportion of cells with EMT signature are associated with a worse prognosis [14]. The SRC protein kinase is a crucial activator of AJ disassembly, that initiates EMT, with elevated activity in EOC patients [15,16].…”

CTDPathSim: Cell line-tumor deconvoluted pathway-based similarity in the context of precision medicine in cancer*

“…In an investigation of functional utility of ovarian cancer cell lines in pre-clinical trial, Coscia et al [50] reported KURAMOCHI as one of the closest resemblance to the tumor samples. A recent study, using deep single cell RNA-Seq data, established this cell line as potential model of ovarian cancer subtype in vitro [51]. Domcke et al [52] reported KURAMOCHI as one of the top cell lines for ovarian tumors.…”

“…Since the known drug screening data between TCGA samples and cell lines were limited, we included structurally similar drugs in our evaluation. We retrieved PaDEL descriptor [49] of drug's chemical properties and 2D and 3D structural profiles of 378 drugs in GDSC using a line notation of simplified molecular-input line entry system (SMILES) [50] from PubChem [51] database. We computed structural similarities using Pearson correlation between different drugs from TCGA and GDSC.…”

CTDPathSim

“…In an investigation of functional utility of ovarian cancer cell lines in pre-clinical trial, Coscia et al [52] reported KURAMOCHI as one of the closest resemblance to the tumor samples. A recent study, using deep single cell RNA-Seq data, established this cell line as potential model of ovarian cancer subtype in vitro [53]. Domcke et al [54] reported KURAMOCHI as one of the top cell lines for ovarian tumors.…”