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Endocrine disruption of early uterine differentiation causes adenocarcinoma mediated by Wnt/β-catenin- and PI3K/AKT signaling

ABSTRACT: Developmental exposure to non-mutagenic environmental factors can contribute to cancer risk, but the underlying mechanisms are not understood. We used a mouse model of endometrial adenocarcinoma that results from brief developmental exposure to an estrogenic chemical, diethylstilbestrol (DES), to determine causative factors. Single cell RNA sequencing and spatial transcriptomics of adult uteri revealed new markers of uterine epithelial stem cells, identified luminal and glandular progenitor cells, and defined a glandular epithelial differentiation trajectory. Neonatal DES exposure disrupted uterine epithelial differentiation, resulting in widespread activation of Wnt signaling and a failure to generate epithelial stem cells or distinguishable glandular and luminal epithelial cells. The endometrial stromal cells activated inflammatory signals and oxidative stress. Together, these changes activated PI3K/AKT signaling to drive malignant transformation. These findings explain how human cancers, which are often associated with abnormal activation of PI3K/AKT signaling, could result from exposure to environmental insults during development.

ORGANISM(S): Mus musculus

PROVIDER: GSE218156 | GEO | 2023/08/11

REPOSITORIES: GEO

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SIX1 regulates aberrant endometrial epithelial cell differentiation and cancer latency following developmental estrogenic chemical exposure

Project description:Female mice exposed neonatally to the synthetic estrogen diethylstilbestrol (DES) develop metaplastic and neoplastic uterine changes as adults. Abnormal endometrial glands express the oncofetal protein sine oculis homeobox 1 (SIX1) and contain cells with basal (cytokeratin [CK]14+/18-) and poorly differentiated features (CK14+/18+), strongly associating SIX1 with aberrant differentiation and cancer. Here we tested whether SIX1 expression is necessary for abnormal endometrial differentiation and DES-induced carcinogenesis by using Pgr-cre to generate conditional knockout mice lacking uterine Six1 (Six1d/d). Interestingly, corn oil (CO) vehicle treated Six1d/d mice develop focal endometrial glandular dysplasia and features of carcinoma in situ as compared with CO wildtype Six1 (Six1+/+) mice. Furthermore, Six1d/d mice neonatally exposed to DES had a 42% higher incidence of endometrial cancer relative to DES Six1+/+ mice. While DES Six1d/d mice had >10-fold fewer CK14+/18- basal cells within the uterine horns as compared with DES Six1+/+ mice, the appearance of CK14+/18+ cells remained a feature of neoplastic lesions. We have employed whole genome microarray expression profiling as a discovery platform to identify genes associated with the phenotypic changes described above. Expression of three genes (Ihh, Krt14, and Trp63) were quantified by real-time PCR, confirming low variability between samples as well as the predicted response pattern.

2019-10-15 | GSE138501 | GEO

Reconstructing Lineage Hierarchies of Mice Uterus Epithelia Development using Single Cell Analysis

Project description:Purpose:The endometrium layer comprises of luminal and glandular epithelia that both develop from the same simple layer of fetal uterine epithelia. Mechanisms of uterine epithelial progenitor self-renewal and differentiation are unclear. Methods: This study aims to systematically analyze the molecular and cellular mechanisms of uterine epithelia development by single cell RNA-Seq Results: An integrated set of single cell transcriptomic data of uterine epithelial progenitors and their differentiated progenies is provided. Additionally, the unique molecular signatures of these cells, characterized by sequential up-regulation of specific epigenetic and metabolic activities, and activation of unique signaling pathways and transcription factors, were also investigated. Finally, a unique subpopulation of early progenitor, as well as differentiated luminal and glandular lineages were identified. A complex cellular hierarchy of uterine epithelia development was thus delineated. Conclusions: Our study therefore systematically decoded molecular markers and cellular program of uterine epithelia development that would shed lights on uterine developmental biology.

2017-06-30 | GSE98451 | GEO

Neonatal diethylstilbestrol exposure alters the metabolic profile of uterine epithelial cells.

Project description:Developmental exposure to diethylstilbestrol (DES) causes reproductive tract malformations, affects fertility and increases the risk of clear cell carcinoma of the vagina and cervix in humans. Previous studies on a well-established mouse DES model demonstrated that it recapitulates many features of the human syndrome, yet the underlying molecular mechanism is far from clear. Using the neonatal DES mouse model, the present study uses global transcript profiling to systematically explore early gene expression changes in individual epithelial and mesenchymal compartments of the neonatal uterus. Over 900 genes show differential expression upon DES treatment in either one or both tissue layers. Interestingly, multiple components of the Peroxisome Proliferator-Activated Receptor gamma (PPAR gamma)-mediated adipogenic/lipid metabolic pathway, including PPARgamma itself, are targets of DES in the neonatal uterus. TEM and Oil Red O staining further demonstrate a dramatic increase in lipid deposition in the uterine epithelial cells upon DES exposure. Neonatal DES exposure also perturbs glucose homeostasis in the uterine epithelium. Some of these neonatal DES-induced metabolic changes appear to last into adulthood, suggesting a permanent effect of DES on energy metabolism in uterine epithelial cells. This study extends the list of biological processes that can be regulated by estrogen or DES, and provides a novel perspective for endocrine disruptor induced reproductive abnormalities.

2012-05-15 | GSE37969 | GEO

Gene expression profiling of mouse prostate over-expressing the Notch1 intracellular domain.

Project description:Molecular signaling that regulates differentiation, survival and proliferation of the prostate luminal epithelial cells has not been thoroughly understood. Herein, we show that increased canonical Notch1 activity suppresses terminal differentiation of prostate luminal epithelial cells but is insufficient to transform. Augmented Notch1 activity delays anoikis of luminal epithelial cells by augmenting NF-κB activity independent of Hes-1, stimulates luminal cell proliferation by potentiating the PI3K-AKT signaling, and rescues the capacities of a fraction of prostate luminal epithelial cells for unipotent differentiation in vivo and short-term self-renewal in vitro. Epithelial cell-autonomous AR signaling is dispensable for the Notch-mediated cellular survival and proliferation. This study reveals a previously unappreciated role of Notch in prostatic luminal epithelial cell differentiation, supports the presence of a lineage hierarchy within the prostate luminal epithelial cells, and implies a pro-metastatic function of Notch signaling during prostate cancer progression. Two group comparison (WT and Mut)

2014-08-07 | E-GEOD-53036 | biostudies-arrayexpress

RNASeq PROFILES RELATED TO ENDOMETRIAL HEALTH

Project description:In postpartum dairy cows, subclinical endometritis (SCE) is characterized by persistent endometrial inflammation, which exerts profound detrimental effects on subsequent reproductive performance. So far, transcriptomic studies related to this condition were either based on biopsy-derived whole endometrium tissue or endometrial swab/cytobrush samples, thus neglecting cell type-specific variations in gene expression. This study tested the hypothesis that different endometrial health statuses are associated with distinct transcription profiles of endometrial stromal, glandular and luminal epithelial cells. In conclusion, this study evidences that endometrial inflammation recovery or persistence is associated with gene expression patterns involved in immune function, tissue remodelling, and uterine receptivity in a cell type-specific manner. Identifying these signatures may prove instrumental to developing novel diagnostic and therapeutic targets, either to prevent persistence or speed recovery from endometrial inflammation, thus restoring the fertility of postpartum dairy cows.

2022-04-20 | GSE192545 | GEO

The analysis of the α2,6-sialylated proteins in endometrium from porcine gestational day 15 by LC-MS/MS

Project description:Implantation is the attachment of embryo in the endometrium. Failure in implantation is a major cause of early pregnancy loss. During implantation, the temporal uterine lumen closure can help embryo attach to the uterus. In pigs, extending of endometrial folds to form interlocking finger-like projections is a main cause leads to uterine lumen closure during attachment time, but the underlying mechanisms are largely unknown. Our data reveal that pig uterine luminal epithelium (LE) migrate in coordinated groups during extending of endometrial folds. Moreover, the MALDI-TOF MS based N-glycomic characterization of porcine endometrium revealed α2,6-linked sialic acid are highly expressed in pig uterine LE during extending of endometrial folds. To investigated the mechanisms by which α2,6-sialylated proteins in formation of the endometrial folding during implantation in pigs, the α2,6-sialylated proteins in pig uterine LE were characterized by proteomic analysis and those proteins that are involved in cell adhesion, such as E-cadherin, were detected. Finally, our in vivo and in vitro data show that α2,6-sialylation of E-cadherin occurs in accompany with collective epithelial migration. The results provide new insight into the mechanism of pig implantation by identifying that α2,6-sialylation of cell adhesion molecules may participate in formation of extending of endometrial folds through promoting of collective migration of uterine LE.

2022-02-17 | PXD027571 | Pride

Spatial Transcriptomics Analysis of Uterine Gene Expression in Enhancer of Zeste Homolog 2 (Ezh2) Conditional Knockout Mice

Project description:Histone proteins undergo various modifications that alter chromatin structure, including addition of methyl groups. Enhancer of homolog 2 (EZH2), is a histone methyltransferase that methylates lysine residue 27, and thereby, suppresses gene expression. EZH2 plays integral role in the uterus and other reproductive organs. We have previously shown that conditional deletion of uterine EZH2 results in increased proliferation of luminal and glandular epithelial cells, and RNAseq analyses reveal several uterine transcriptomic changes in Ezh2 conditional (c) knockout (KO) mice that can affect estrogen signaling pathways. To pinpoint the origin of such gene expression changes, we used the recently developed spatial transcriptomics (ST) method with the hypotheses that Ezh2cKO mice would predominantly demonstrate changes in epithelial cells and/or ablation of this gene would disrupt normal epithelial/stromal gene expression patterns. Uteri were collected from ovariectomized adult WT and Ezh2cKO mice and analyzed by ST. Asb4, Cxcl14, Dio2, and Igfbp5 were increased, Sult1d1, Mt3, and Lcn2 were reduced in Ezh2cKO uterine epithelium vs. WT epithelium. For Ezh2cKO uterine stroma, differentially expressed key hub genes included Cald1, Fbln1, Myh11, Acta2, and Tagln. Conditional loss of uterine Ezh2 also appears to shift the balance of gene expression profiles in epithelial vs. stromal tissue toward uterine epithelial cell and gland development and proliferation, consistent with uterine gland hyperplasia in these mice. Current findings provide further insight into how EZH2 may selectively affect uterine epithelial and stromal compartments. Additionally, these transcriptome data might provide the mechanistic understanding and valuable biomarkers for human endometrial disorders with epigenetic underpinnings.

2021-08-17 | GSE181885 | GEO

Gene expression profiling of mouse prostate over-expressing the Notch1 intracellular domain.

2014-08-07 | GSE53036 | GEO

Neonatal diethylstilbestrol exposure alters the metabolic profile of uterine epithelial cells.

2012-05-14 | E-GEOD-37969 | biostudies-arrayexpress

ARID1A and PI3-Kinase pathway mutations in the endometrium drive epithelial transdifferentiation and collective invasion [12Z_RNA-seq]

Project description:ARID1A and PI3-Kinase (PI3K) pathway alterations are common in neoplasms originating from the uterine endometrium. Here we show that monoallelic loss of ARID1A in the mouse endometrial epithelium is sufficient for vaginal bleeding when combined with PI3K activation. Sorted mutant epithelial cells display gene expression and promoter chromatin signatures associated with epithelial-to-mesenchymal transition (EMT). We further show that ARID1A is bound to promoters with open chromatin, but ARID1A loss leads to increased promoter chromatin accessibility and the expression of EMT genes. PI3K activation partially rescues the mesenchymal phenotypes driven by ARID1A loss through antagonism of ARID1A target gene expression, resulting in partial EMT and invasion. We propose that ARID1A normally maintains endometrial epithelial cell identity by repressing mesenchymal cell fates, and that coexistent ARID1A and PI3K mutations promote epithelial transdifferentiation and collective invasion. Broadly, our findings support a role for collective epithelial invasion in the spread of abnormal endometrial tissue.

2019-07-01 | GSE129782 | GEO

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