Transcriptional landscape of BE disease progression
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE158116 | GEO | 2020/09/17
REPOSITORIES: GEO
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Project description:Esophageal adenocarcinoma (EAC) has the fastest increase of any cancer in the US and Europe, and arises in the setting of BarrettM-bM-^@M-^Ys esophagus (BE), defined by replacement of normal squamous epithelium with columnar intestinal-like epithelium. BE is thought to result from chronic esophageal inflammation but has been elusive to model in animals. Herein, we have generated the first transgenic mouse model of BarrettM-bM-^@M-^Ys esophagus through overexpression of interleukin-1M-CM-^_ (IL-1M-NM-2). IL-1M-NM-2 overexpression in the mouse esophageal mucosa induces chronic inflammation that progresses to intestinal metaplasia, with characteristic expression of TFF2, Bmp4 and Cdx2. With aging, IL-1b transgenic mice progress to esophageal adenocarcinoma (EAC) but the process is markedly accelerated by exposure to bile acids and/or nitrosamines, resembling the human counterpart. Moreover, progenitor cells present in the gastric cardia, but absent from the esophagus in humans and mice, are increased in BE, suggesting the cell of origin in the gastric cardia Comparison of BE and EAC tissue from the mouse with normal squamous epithelium from the mouse.
2011-01-31 | E-GEOD-24931 | biostudies-arrayexpress
Project description:The gastroesophageal squamocolumnar junction (GE-SCJ) is a critical tissue interface between the esophagus and stomach, with significant relevance in the pathophysiology of gastrointestinal diseases. Despite this, the molecular mechanisms underlying GE-SCJ development remain unclear. Using single-cell transcriptomics, organoids, and spatial analysis, we examine the cellular heterogeneity and spatiotemporal dynamics of GE-SCJ development from embryonic to adult mice. We identify distinct transcriptional states and signaling pathways in the epithelial and mesenchymal compartments of the esophagus and stomach during development. Fibroblast-epithelial interactions are mediated by various signaling pathways, including WNT, BMP, TGF-β, FGF, EGF, and PDGF. Our results suggest that fibroblasts predominantly send FGF and TGF-β signals to the epithelia, while epithelial cells mainly send PDGF and EGF signals to fibroblasts. We observe differences in the ligands and receptors involved in cell-cell communication between the esophagus and stomach. Our findings provide insights into the molecular mechanisms underlying GE-SCJ development and fibroblast-epithelial crosstalk involved, paving the way to elucidate mechanisms during adaptive metaplasia development and carcinogenesis.
2024-03-12 | GSE227412 | GEO
Project description:The gastroesophageal squamocolumnar junction (GE-SCJ) is a critical tissue interface between the esophagus and stomach, with significant relevance in the pathophysiology of gastrointestinal diseases. Despite this, the molecular mechanisms underlying GE-SCJ development remain unclear. Using single-cell transcriptomics, organoids, and spatial analysis, we examine the cellular heterogeneity and spatiotemporal dynamics of GE-SCJ development from embryonic to adult mice. We identify distinct transcriptional states and signaling pathways in the epithelial and mesenchymal compartments of the esophagus and stomach during development. Fibroblast-epithelial interactions are mediated by various signaling pathways, including WNT, BMP, TGF-β, FGF, EGF, and PDGF. Our results suggest that fibroblasts predominantly send FGF and TGF-β signals to the epithelia, while epithelial cells mainly send PDGF and EGF signals to fibroblasts. We observe differences in the ligands and receptors involved in cell-cell communication between the esophagus and stomach. Our findings provide insights into the molecular mechanisms underlying GE-SCJ development and fibroblast-epithelial crosstalk involved, paving the way to elucidate mechanisms during adaptive metaplasia development and carcinogenesis.
2024-03-12 | GSE181409 | GEO
Project description:The gastroesophageal squamocolumnar junction (GE-SCJ) is a critical tissue interface between the esophagus and stomach, with significant relevance in the pathophysiology of gastrointestinal diseases. Despite this, the molecular mechanisms underlying GE-SCJ development remain unclear. Using single-cell transcriptomics, organoids, and spatial analysis, we examine the cellular heterogeneity and spatiotemporal dynamics of GE-SCJ development from embryonic to adult mice. We identify distinct transcriptional states and signaling pathways in the epithelial and mesenchymal compartments of the esophagus and stomach during development. Fibroblast-epithelial interactions are mediated by various signaling pathways, including WNT, BMP, TGF-β, FGF, EGF, and PDGF. Our results suggest that fibroblasts predominantly send FGF and TGF-β signals to the epithelia, while epithelial cells mainly send PDGF and EGF signals to fibroblasts. We observe differences in the ligands and receptors involved in cell-cell communication between the esophagus and stomach. Our findings provide insights into the molecular mechanisms underlying GE-SCJ development and fibroblast-epithelial crosstalk involved, paving the way to elucidate mechanisms during adaptive metaplasia development and carcinogenesis.
2024-03-12 | GSE181411 | GEO
Project description:Esophageal adenocarcinoma (EAC) has the fastest increase of any cancer in the US and Europe, and arises in the setting of Barrett’s esophagus (BE), defined by replacement of normal squamous epithelium with columnar intestinal-like epithelium. BE is thought to result from chronic esophageal inflammation but has been elusive to model in animals. Herein, we have generated the first transgenic mouse model of Barrett’s esophagus through overexpression of interleukin-1ß (IL-1β). IL-1β overexpression in the mouse esophageal mucosa induces chronic inflammation that progresses to intestinal metaplasia, with characteristic expression of TFF2, Bmp4 and Cdx2. With aging, IL-1b transgenic mice progress to esophageal adenocarcinoma (EAC) but the process is markedly accelerated by exposure to bile acids and/or nitrosamines, resembling the human counterpart. Moreover, progenitor cells present in the gastric cardia, but absent from the esophagus in humans and mice, are increased in BE, suggesting the cell of origin in the gastric cardia
2011-01-31 | GSE24931 | GEO
Project description:The squamous–columnar junction (SCJ) is a boundary consisting of precisely positioned transitional epithelium between the squamous and columnar epithelium. Transitional epithelium is a hotspot for precancerous lesions, and is therefore clinically important; however, the origins and physiological properties of transitional epithelium have not been fully elucidated. Here, by using mouse genetics, lineage tracing, and organoid culture, we examine the development of the SCJ in the mouse stomach, and thus define the unique features of transitional epithelium. We find that two transcription factors, encoded by Sox2 and Gata4, specify primitive transitional epithelium into squamous and columnar epithelium. The proximal–distal segregation of Sox2 and Gata4 expression establishes the boundary of the unspecified transitional epithelium between committed squamous and columnar epithelium. Mechanistically, Gata4-mediated expression of the morphogen Fgf10 in the distal stomach and Sox2-mediated Fgfr2 expression in the proximal stomach induce the intermediate regional activation of MAPK/ERK, which prevents the differentiation of transitional epithelial cells at the SCJ boundary. Our results have implications for tissue regeneration and tumorigenesis, which are related to the SCJ.
2020-12-17 | GSE143217 | GEO
Project description:Patients were recruited at the Departments of Abdominal Surgery and Endoscopy of the Hospital do Cancer AC Camargo (São Paulo/Brazil) during a 4-year period (2001 to 2004). All patients signed a pre-informed consent and the study was approved by the internal ethics committee. Tissue samples were either snap frozen in liquid nitrogen (when obtained by surgery) or collected in RNAlaterTM (Ambion®, Austin, Texas USA, when obtained by biopsy). For all samples, diagnosis was confirmed by H&E staining at the time of RNA extraction. Biopsy samples of the esophageal and gastric mucosa obtained by endoscopy had information of the correct anatomical location using a standard diagram. Frozen samples were dissected and only those having at least 70% of tumor cells were processed. A total of 71 samples were analyzed: 39 esophagus and esophagogastric junction samples (9 normal mucosa, 6 esophagitis mucosa, 10 Barrett's mucosa - 4 for the long type and 6 for the short type, and 14 tumor samples of adenocarcinoma) and 32 stomach samples (6 normal body and antrum mucosa, 5 normal cardiac mucosa, 9 intestinal metaplasia mucosa, 7 samples of intestinal type adenocarcinoma and 5 samples of diffuse type carcinoma). For Barrett's samples, diagnosis required evidence of intestinal metaplasia together with tongues or segments of red columnar-appearing epithelium extending upwards from the esophagogastric junction. A long Barrett's esophagus was defined as longer ?3cm and a short Barrett's esophagus by ?3cm of columnar epithelium (Spechler, 2004). The tumor samples of esophagus and esophagogastric junction were not differentiated. For the gastric adenocarcinoma samples were used the Laurén's classification (Laurén, 1965) and the others gastric sample were previously described (Meireles et al, 2003). Keywords: other
2005-05-09 | GSE2444 | GEO
Project description:In this study, we used RNA sequencing to characterize esophageal progenitors following activation of the hedgehog (HH) pathway in vivo. We observed two main fates following activation of the HH pathway in the squamous epithelium: one population is in an intermediate state between squamous and columnar epithelium, and another achieves a full columnar conversion. We compared these 2 populations to different FACS sorted epithelial cells from different tissues of the gastro-intestinal tract (adult esophagus, embryonic esophagus, transition epithelium from the stomach, corpus of the stomach and small intestine). Our results suggest a multistep process in which esophageal progenitors first turn on a transcriptomic program that resembles the one from embryonic esophagus, then, a subset of these dedifferentiated cells can turn on a columnar differentiation program that shares similarities with intestinal cells. Collectively, these data demonstrate that some esophageal cells can be reprogrammed to generate columnar cells in vivo.
2021-04-20 | GSE148874 | GEO
Project description:The requirement of goblet cells (intestinal metaplasia; IM) to define BarrettM-bM-^@M-^Ys esophagus (BE) remains controversial as some studies have shown that the risk of progression to esophageal adenocarcinoma (EAC) is similar for non-goblet cell metaplasia (NGM) and IM. IM harbors genomic aberrations in known cancer-associated genes and these have been linked to increased EAC risk. No detailed studies have explored DNA alterations in NGM. We hypothesized that a comparison of DNA alterations in cancer-associated genes in IM and NGM samples would provide insight into their relative risks for progression to EAC. Patient biopsies were analyzed using Affymetrix SNP 6.0 arrays, FISH, and targeted resequencing of 20 frequently mutated EAC genes. Frequent CNAM-bM-^@M-^Ys targeting cancer-associated genes were found in IM whereas no such changes were observed in NGM. In one subject, FISH confirmed loss of CDKN2A and amplification of chromosome 8 in IM but not in a nearby NGM biopsy. Targeted sequencing in a subset of metaplasia tissues revealed 11 non-synonymous mutations in 16 IM samples and 2 mutations in 19 NGM samples. Our results show that IM has a much higher frequency of cancer-associated mutations than NGM and is therefore likely to pose a higher risk for development of EAC. 57 non-goblet metaplasia, intestinal metaplasias, and composite specimens from 45 subjects were studied. DNA copy number abnormalities (CNAM-bM-^@M-^Ys) were identified using Affymetrix arrays and fluorescence in situ hybridization (FISH). Data was processed in Nexus 6.0 (BioDiscovery, CA). Targeted sequencing of all exons from twenty genes found to be frequently mutated in EAC was performed on metaplasia samples using Ion AmpliSeqM-bM-^DM-" DNA sequencing.
2012-12-15 | E-GEOD-40769 | biostudies-arrayexpress
Project description:Esophageal adenocarcinoma (EAC) has become a major concern in Western countries due to rapid rises in incidence coupled with very poor survival rates. One of the key risk factors for the development of this cancer is the presence of Barrett’s esophagus (BE), which is believed to form in response to repeated gastro-esophageal reflux. In this study we performed comparative, genome-wide expression profiling (using Illumina whole-genome Beadarray) on total RNA extracted from esophageal biopsy tissues from individuals with EAC, BE (in the absence of EAC) and those with normal squamous epithelium. We combined these data with publically accessible raw data from three similar studies to investigate key gene and ontology differences between these three tissue states. The results support the deduction that BE is a tissue with enhanced glycoprotein synthesis machinery (DPP4, ATP2A3, AGR2) designed to provide strong mucosal defenses aimed at resisting gastro-esophageal reflux. EAC exhibits the enhanced extracellular matrix remodeling (collagens, IGFBP7, PLAU) effects expected in an aggressive form of cancer, as well as evidence of reduced expression of genes associated with mucosal (MUC6, CA2, TFF1) and xenobiotic (AKR1C2, AKR1B10) defenses. When our results are compared to previous whole-genome expression profiling studies keratin, mucin, annexin and trefoil factor gene families are the most frequently represented gene families. Eleven genes identified here are also represented in at least 3 other profiling studies. We used these genes to discriminate squamous, BE and EAC within the two largest cohorts using a support vector machine leave one out cross validation analysis. While this method was satisfactory for discriminating squamous and BE, it demonstrates the need for more detailed investigations into profiling changes within BE leading to the progression towards EAC. A comparison of three esophageal biopsy groups from separate individuals: normal squamous (n=9), Barrett's esophagus without dysplasia (n=22) & adenocarcinoma (n=23). Adenocarcinoma samples overlap with members of DNA copy number analysis GEO series GSE10506 such that, in each case genomic DNA and total RNA were extracted from the same biopsy. The matching copy number data GEO samples IDs are noted in characteristics: Matching CN Sample ID
2011-08-16 | E-GEOD-28302 | biostudies-arrayexpress