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PAX2-null progenitors define multiple lineages with common expression signatures in benign and neoplastic oviductal epithelium

ABSTRACT: The oviducts contain high grade serous cancer precursors, which are γ-H2AXp and p53 mutation positive. Secretory cell outgrowths (SCOUTs) are associated with older age and serous cancer. We evaluated PAX2 expression in proliferating oviductal cells, normal mucosa, SCOUTs, Walthard cell nests, STINs and HGSCs. Non-ciliated cells in normal mucosa were PAX2 positive but became PAX2 negative in multilayered epithelium. PAX2 negative SCOUTs fell into two groups; Type I were secretory or secretory/ciliated with a “tubal” phenotype and were ALDH1 negative. Type II displayed a columnar to pseudostratified phenotype, with an EZH2,ALDH1, β-catenin, Stathmin, LEF1, RCN1 and RUNX2 expression signature . This study, for the first time, links PAX2 negative with proliferating fetal and adult oviductal cells undergoing basal and ciliated differentiation and shows that this expression state is maintained in SCOUTs, STINs and HGSCs. All three entities can demonstrate a consistent perturbation of genes involved in potential tumor suppressor gene silencing (EZH2), transcriptional regulation (LEF1), regulation of differentiation (RUNX2) calcium binding (RCN1) and oncogenesis (Stathmin). This shared expression signature between benign and neoplastic entities links normal progenitor cell expansion to abnormal and neoplastic outgrowth in the oviduct and exposes a common pathway that could be a target of early prevention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE58842 | GEO | 2014/09/20

SECONDARY ACCESSION(S): PRJNA253680

REPOSITORIES: GEO

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PAX2-null progenitors define multiple lineages with common expression signatures in benign and neoplastic oviductal epithelium

Project description:The oviducts contain high grade serous cancer precursors, which are M-NM-3-H2AXp and p53 mutation positive. Secretory cell outgrowths (SCOUTs) are associated with older age and serous cancer. We evaluated PAX2 expression in proliferating oviductal cells, normal mucosa, SCOUTs, Walthard cell nests, STINs and HGSCs. Non-ciliated cells in normal mucosa were PAX2 positive but became PAX2 negative in multilayered epithelium. PAX2 negative SCOUTs fell into two groups; Type I were secretory or secretory/ciliated with a M-bM-^@M-^\tubalM-bM-^@M-^] phenotype and were ALDH1 negative. Type II displayed a columnar to pseudostratified phenotype, with an EZH2,ALDH1, M-NM-2-catenin, Stathmin, LEF1, RCN1 and RUNX2 expression signature . This study, for the first time, links PAX2 negative with proliferating fetal and adult oviductal cells undergoing basal and ciliated differentiation and shows that this expression state is maintained in SCOUTs, STINs and HGSCs. All three entities can demonstrate a consistent perturbation of genes involved in potential tumor suppressor gene silencing (EZH2), transcriptional regulation (LEF1), regulation of differentiation (RUNX2) calcium binding (RCN1) and oncogenesis (Stathmin). This shared expression signature between benign and neoplastic entities links normal progenitor cell expansion to abnormal and neoplastic outgrowth in the oviduct and exposes a common pathway that could be a target of early prevention. 17 total samples are analyzed. 4 for TYPE 1 SCOUTs, 3 for TYPE 2 SCOUTs, 7 for paired normal epithelium, 3 for tumor

2014-09-20 | E-GEOD-58842 | biostudies-arrayexpress

Expression data from mouse ALDH1 positive and ALDH1 negative ovarian surface epithelium (OSE) cells

2013-01-31 | GSE43897 | GEO

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

Project description:The human fallopian tube harbors the cell-of-origin for the majority of high-grade serous “ovarian” cancers (HGSCs), but its cellular composition, particularly of the epithelial component, is poorly characterized. We subjected 12 fallopian specimens from 8 patients to single-cell transcriptomic profiling, analyzing around 53,000 individual cells to map the major immune, fibroblastic and epithelial cell types present in this organ. We identified 10 epithelial sub-populations, characterized by diverse transcriptional programs including SOX17 (enriched in secretory epithelial cells), TTF3 and RFX3 (enriched in ciliated cells) and NR2F2 (enriched in early, partially differentiated secretory cells). Based on transcriptional signatures, we reconstructed a trajectory whereby secretory cells differentiate into ciliated cells via a RUNX3high intermediate. Computational deconvolution of the cellular composition of advanced HGSCs based on epithelial subset signatures identified the ‘early secretory’ population as a likely precursor state for the majority of HGSCs. The signature of this rare population of cells comprised both epithelial (EPCAM, KRT) and mesenchymal (THY1, ACTA2) features, and was enriched in mesenchymal-type HGSCs (P = 6.7 x 10e-27), a group known to have particularly poor prognoses. This cellular and molecular compendium of the human fallopian tube in cancer-free women is expected to advance our understanding of the earliest stages of fallopian epithelial neoplasia.

2021-04-19 | GSE151214 | GEO

Expression data from mouse ALDH1 positive and ALDH1 negative ovarian surface epithelium (OSE) cells

Project description:The hilum region of the mouse ovary, the transitional/junction area between OSE, mesothelium and tubal (oviductal) epithelium is identified as a previously unrecognized stem cell niche of the OSE. OSE cells with high ALDH1 activity have been predominantly detected in the hilum region by immunohistochemical staining. For additional phenotypical characterization, we used microarrays to detail the gene expression profiling between the ALDH1 positive and ALDH1 negative OSE cells. Three independent pools (10 mice each) were analyzed. ALDH1 positive and ALDH negative OSE cells were isolated by FACS and their mRNA used for hybridization onto Affymetrix Mouse Genome 430 2.0 array. Microarray data were analyzed with GeneSifter software. To identify genes significantly altered in ALDH positive population, we performed paired two group analysis with Significance Analysis of Microarrays (SAM) software and visualized with Treeview software.

2013-01-31 | E-GEOD-43897 | biostudies-arrayexpress

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

Project description:The human fallopian tube harbors the cell-of-origin for the majority of high-grade serous ‘ovarian’ cancers (HGSCs), but its cellular composition, particularly of the epithelial component, is poorly characterized. We performed single-cell transcriptomic profiling in 12 primary fallopian specimens from 8 patients, analyzing around 53,000 individual cells to map the major immune, fibroblastic and epithelial cell types present in this organ. We identified 10 epithelial sub-populations, characterized by diverse transcriptional programs including SOX17 (enriched in secretory epithelial cells), TTF3 and RFX3 (enriched in ciliated cells) and NR2F2 (enriched in early, partially differentiated secretory cells). Based on transcriptional signatures, we reconstructed a trajectory whereby secretory cells differentiate into ciliated cells via a RUNX3high intermediate. Computational deconvolution of the cellular composition of advanced HGSCs based on epithelial subset signatures identified the ‘early secretory’ population as a likely precursor state for the majority of HGSCs. The signature of this rare population of cells comprised both epithelial (EPCAM, KRT) and mesenchymal (THY1, ACTA2) features, and was enriched in mesenchymal-type HGSCs (P = 6.7 x 10-27), a group known to have particularly poor prognoses. This cellular and molecular compendium of the human fallopian tube in cancer-free women is expected to advance our understanding of the earliest stages of fallopian epithelial neoplasia. PAX8, SOX17, MECOM, and WT1 are critical genes in high-grade ovarian cancer tumorigenesis. However, the target genes of these factors in a normal to tumor context is unknown. Depletion of these factors in fallopian tube secretory epithelial and high-grade serous ovarian cancer cells revealed transcription factor and cell-type dependent differential expression patterns.

2021-04-19 | GSE151316 | GEO

Single cell RNA sequencing of normal endometrial derived organoids uncovers novel cell type markers for prognostication

Project description:Endometrial carcinoma, the most common gynecologic cancer, develops from endometrial epithelium which is composed of secretory and ciliated cells. Pathologic classification is unreliable and there is a need for prognostic tools. We used single cell sequencing to study organoid model systems derived from normal endometrial endometrium to discover novel markers specific for endometrial ciliated or secretory cells. We performed single cell sequencing on endometrial and ovarian tumors and found both secretory-like and ciliated-like tumor cells.

| EGAS00001004466 | EGA

ena-DATASET-BCCRC-MO-09-07-2020-19:34:17:220-1310 - samples

Project description:Endometrial carcinoma, the most common gynecologic cancer, develops from endometrial epithelium which is composed of secretory and ciliated cells. Pathologic classification is unreliable and there is a need for prognostic tools. We used single cell sequencing to study organoid model systems derived from normal endometrial endometrium to discover novel markers specific for endometrial ciliated or secretory cells. We performed single cell sequencing on endometrial and ovarian tumours, and on organoids both treated with DBZ and normal and found both secretory-like and ciliated-like tumour cells.

| EGAD00001006280 | EGA

Effects of Myb shRNA on Airway Epithelial Cells

Project description:The epithelium of the pulmonary airway is specially differentiated to provide defense against environmental insults, but also subject to dysregulated differentiation that results in lung disease. The current paradigm for airway epithelial differentiation is a one-step program whereby a p63+ basal epithelial progenitor cell generates a ciliated or secretory cell lineage, but the cue for this transition and whether there are intermediate steps is poorly defined. Here we identify transcription factor Myb as a key regulator that permits early multilineage differentiation of airway epithelial cells. Myb+ cells were identified as p63– and therefore distinct from basal progenitor cells, but were still negative for markers of differentiation. Myb RNAi treatment of primary-culture airway epithelial cells and Myb gene deletion in mice resulted in a p63– population with failed maturation of Foxj1+ ciliated cells, as well as Scbg1a1+ and Muc5ac+ secretory cells. Consistent with these findings, analysis of whole genome expression of Myb-deficient cells identified Myb-dependent programs for ciliated and secretory cell differentiation. Myb+ cells were rare in human airways but were increased in regions of ciliated cells and mucous cell hyperplasia in samples from subjects with chronic obstructive pulmonary disease. Together, the results show that a p63– Myb+ population of airway epithelial cells represents a distinct intermediate stage of differentiation that is required under normal conditions and may be heightened in airway disease. 12 samples, 2x2 factorial design, factor 1: time (days post-ALI), factor 2:shRNA (Myb vs Scrambled Control), performed in triplicate (biological replicates)

2014-08-12 | E-GEOD-60365 | biostudies-arrayexpress

Activation of Notch1 and Notch3 Skews Human Airway Basal Cell Differentiation Toward a Secretory Pathway

Project description:Airway basal cells (BC) function as progenitor cells capable of differentiating into ciliated and secretory cells to replenish the airway epithelium during physiological turnover and repair. The objective of this study was to define the role of Notch signaling in regulating human airway BC differentiation into a pseudostratified mucociliated epithelium. Notch inhibition with γ-secretase inhibitors demonstrated Notch activation is essential for BC differentiation into secre-tory cells and ciliated cells, but more so for the secretory lineage. Sustained Notch activation via lentivirus expression of the intracellular domain of each Notch receptor (NICD1-4) demonstrated that the Notch 2 and 4 pathways have little effect on BC differentiation, while activation of the Notch1 or 3 pathways has a major influence, with persistent expression of NICD1 or 3 resulting in a skewing toward secretory cell differentiation with a parallel decrease in ciliated cell differentiation. These observations provide insights into the control of the balance of BC differentiation into the secretory vs ciliated cell lineage, a balance that is critical for maintaining the normal function of the airway epithelium in barrier defense against the inhaled environment. Array-based expression profiling of the Notch signaling pathway genes specifically in human airway basal cells.

2015-04-13 | E-GEOD-53537 | biostudies-arrayexpress

Effects of Myb shRNA on Airway Epithelial Cells

2014-08-12 | GSE60365 | GEO

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