A Study of High-Grade Serous Ovarian Cancer Origins Implicates the SOX18 Transcription Factor in Tumor Development

Abstract

Highlights d The majority of high-grade serous ovarian cancers arise from fallopian epithelia d A subset of proliferative-type tumors likely arise from ovarian epithelial cells d Super enhancers dysregulate transcription factor expression during tumorigenesis d SOX18 induces an epithelial-to-mesenchymal transition in fallopian tube epithelia

Single-cell Transcriptomics Identifies Gene Expression Networks Driving Differentiation and Tumorigenesis in the Human Fallopian Tube

“…The pseudostratified epithelium of the fallopian tube consists of two major cellular populations. A secretory population that expresses the PAX8 transcription factor is thought to be the predominant cell-of-origin for HGSC (Callahan et al, 2007;Chen et al, 2017;Ducie et al, 2017;Lawrenson et al, 2019;Lee et al, 2007;Medeiros et al, 2006;Meserve et al, 2017). Fallopian secretory epithelia are more proliferative in vitro and in vivo and less competent at repairing DNA damage compared to the FOXJ1-positive ciliated population (Levanon et al, 2010).…”

“…Informed by the characteristics described above, we re-annotated 'Unclassified cluster 1' as 'early secretory', while unclassified clusters 2 and 3 were denoted as 'transitioning' clusters. Using the MuSiC method (Wang et al, 2019) with our combined signatures (see Methods), 6 epithelial signatures were used to deconvolute bulk RNA-seq profiles of 68 FTSEC primary cultures (Lawrenson et al, 2019), to infer the cell subpopulations that preferentially grow in vitro. In 25 out of 68 cultures (39.4%), the 'early secretory' signature was strongly enriched (at least top 25% percentile of estimated frequency, i.e ≥ 0.7 frequency).…”

“…Signatures of secretory cluster 1 and ciliated cells were poorly enriched overall. To see if this pattern is maintained after cellular immortalization with ectopic expression of TERT and mutant TP53, we applied cell type prediction via the label transfer function implemented in Seurat, to map cellular identities from all 10 epithelial subsets in scRNA-seq profiles for the FT282 cell line (Karst et al, 2014;Lawrenson et al, 2019).…”

“…Finally, since the NR2F2 regulon was activated in the early secretory cluster ( Figure 5D), we tested whether this regulon was dysregulated during tumorigenesis using our data set of 68 normal FTSEC ex vivo cultures integrated with 394 HGSCs from TCGA (Lawrenson et al, 2019). Ninety-three genes from the NR2F2 regulon were expressed in our data set ( Figure S6).…”

Genetically Defined, Syngeneic Organoid Platform for Developing Combination Therapies for Ovarian Cancer

“…The cell-of-origin for HGSOC remains controversial. Although transcriptomic (Ducie et al, 2017;Hao et al, 2017;Lawrenson et al, 2019), proteomic (Coscia et al, 2016), epigenomic (Lawrenson et al, 2019), and mouse modeling studies (Szabova et al, 2012;Zhang et al, 2019) suggest that at least some cases initiate in OSE, most HGSOC probably initiates in FTE (Ducie et al, 2017;Karnezis and Cho, 2017;Karnezis et al, 2017). For this reason, we engineered our initial models using FTE organoids.…”