Epithelial-Stromal Interactions in Barrett's Esophagus Modeled in Human Organ Chips.
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ABSTRACT:
SUBMITTER: Shimshoni E
PROVIDER: S-EPMC11308040 | biostudies-literature | 2023
REPOSITORIES: biostudies-literature
Publications
Epithelial-Stromal Interactions in Barrett's Esophagus Modeled in Human Organ Chips.
Shimshoni E E Merry G E GE Milot Z D ZD Oh C Y CY Horvath V V Gould R A RA Caruso J A JA Chen-Tanyolac C C Gascard P P Sangwan V V Bérubé J J Bailey S D SD Hall S S Stachler M D MD Ferri L L Tlsty T D TD Ingber D E DE
Gastro hep advances 20230309 5
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Project description:Esophageal adenocarcinoma is an increasingly common disease with a dismal 5-year survival rate of 10% to 15%. In the first systematic evaluation of the PD-1 pathway in esophageal adenocarcinoma, we identify expression of PD-L2 in cancer cells in 51.7% of esophageal adenocarcinomas. Epithelial PD-L1 was expressed on only 2% of cases, although PD-L1(+) immune cells were observed in 18% of esophageal adenocarcinomas. We also evaluated expression in the precursor lesion of esophageal adenocarcinoma, Barrett's esophagus, which emerges following gastric reflux-induced esophageal inflammation, and found PD-L2 expression in Barrett's esophagus but not in non-Barrett's esophagus esophagitis. Because the progression from squamous esophagitis to Barrett's esophagus is accompanied by a transition from a TH1 to TH2 immune response, we hypothesized that the TH2 cytokines IL4/IL13 could contribute to PD-L2 induction. We confirmed that these cytokines can augment PD-L2 expression in esophageal adenocarcinoma cell lines. These results suggest that the inflammatory environment in Barrett's esophagus and esophageal adenocarcinoma may contribute to the expression of PD-L2. Furthermore, the potential for PD-1 receptor blockade to be effective in esophageal adenocarcinomas with epithelial PD-L2 or immune cell PD-L1 expression should be evaluated in clinical trials.
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Project description:The pathogenesis of subsquamous intestinal metaplasia (SSIM), in which glands of Barrett's esophagus (BE) are buried under esophageal squamous epithelium, is unknown. In a rat model of reflux esophagitis, we found that columnar-lined esophagus developed via a wound-healing process involving epithelial-mesenchymal plasticity (EMP) that buried glands under ulcerated squamous epithelium. To explore a role for reflux-induced EMP in BE, we established and characterized human Barrett's organoids and sought evidence of EMP after treatment with acidic bile salts (AB). We optimized media to grow human BE organoids from immortalized human Barrett's cells and from BE biopsies from seven patients, and we characterized histological, morphological, and molecular features of organoid development. Features and markers of EMP were explored following organoid exposure to AB, with and without a collagen I (COL1) matrix to simulate a wound-healing environment. All media successfully initiated organoid growth, but advanced DMEM/F12 (aDMEM) was best at sustaining organoid viability. Using aDMEM, organoids comprising nongoblet and goblet columnar cells that expressed gastric and intestinal cell markers were generated from BE biopsies of all seven patients. After AB treatment, early-stage Barrett's organoids exhibited EMP with loss of membranous E-cadherin and increased protrusive cell migration, events significantly enhanced by COL1. Using human BE biopsies, we have established Barrett's organoids that recapitulate key histological and molecular features of BE to serve as high-fidelity BE models. Our findings suggest that reflux can induce EMP in human BE, potentially enabling Barrett's cells to migrate under adjacent squamous epithelium to form SSIM.NEW & NOTEWORTHY Using Barrett's esophagus (BE) biopsies, we established organoids recapitulating key BE features. During early stages of organoid development, a GERD-like wound environment-induced features of epithelial-mesenchymal plasticity (EMP) in Barrett's progenitor cells, suggesting that reflux-induced EMP can enable Barrett's cells to migrate underneath squamous epithelium to form subsquamous intestinal metaplasia, a condition that may underlie Barrett's cancers that escape detection by endoscopic surveillance, and recurrences of Barrett's metaplasia following endoscopic eradication therapy.
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Project description:Barrett's esophagus transcriptome was analysed and compared with Barrett's esophagus primary cell culture and esophageal adenocarcinoma. Keywords: SAGE analysis to compare tissues Barrett's esophagus biopsy was taken from 1 male metaplastic Barrett's esophagus patient. Barrett's esophagus primary cell culture was cultures from a biopsy taken from a Barrett's esophagus patient and cultured for about 4 to 5 weeks. Esophageal adenocarcinoma was taken from a patient known to have cancer and previously Barrett's esophagus
2006-06-28 | E-GEOD-5155 | biostudies-arrayexpress
Project description:Barrett's esophagus transcriptome was analysed and compared with Barrett's esophagus primary cell culture and esophageal adenocarcinoma. Keywords: SAGE analysis to compare tissues
2006-06-28 | GSE5155 | GEO
Project description:Barrett's esophagus (BE) increases the risk for development of esophageal adenocarcinoma. Because of the rapid rise in incidence of esophageal adenocarcinoma, screening for BE with subsequent surveillance when found has been proposed as a method of early detection. Sedated endoscopy, however, is too expensive for wide spread screening. As a result, other techniques including unsedated transnasal esophagoscopy and capsule esophagoscopy have been proposed to expand screening programs.
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Project description:ObjectivesSeveral single-nucleotide polymorphisms (SNPs) have been associated with Barrett's esophagus (BE) risk. In addition, environmental factors including smoking, alcohol consumption, and heartburn increase BE risk. However, data on potential interactions between these genetic and environmental factors on BE risk are scant. Understanding how genes and environmental risk factors interact may provide key insight into the pathophysiology of BE, and potentially identify opportunities for targeted prevention and treatment. The objectives of this study were to examine the main effects and the potential effect modification between known genetic loci (SNPs) and established environmental risk factors for BE.MethodsWe performed a nested case-control study using data on 401 incident BE cases and 436 age-matched controls from the Nurses' Health Study, Nurses' Health Study II, and Health Professionals Follow-up Study cohorts, who gave blood and completed biennial questionnaires. Overall, we genotyped 46 SNPs identified in previous BE genome-wide association studies as well as SNPs in candidate genes related to BE susceptibility (i.e., related to excess body fat, fat distribution, factors associated with insulin resistance, and inflammatory mediators). A genetic risk score (GRS) was constructed to evaluate the combined effect of the selected SNPs on BE risk. Interactions between SNPs and BE risk factors were also assessed.ResultsWe observed a suggestive, but not statistically significant, association between our GRS and BE risk: a one-allele increase in the unweighted GRS increased the risk of BE by a factor of 1.20 (95% confidence interval = 1.00-1.44; P = 0.057). We did not observe any meaningful multiplicative interactions between smoking, alcohol consumption, or heartburn duration and BE genotypes. When we assessed the joint effect of weighted GRS and BE risk factors, we did not observe any significant interaction with alcohol and heartburn duration, whereas smoking showed a significant multiplicative interaction (P = 0.016).ConclusionsOur results suggest that SNPs associated with BE at genome-wide significant levels can be combined into a GRS with a potential positive association with BE risk.
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Project description:As the premalignant lesion of human esophageal adenocarcinoma (EAC), Barrett's esophagus (BE) is characterized by intestinal metaplasia in the normal esophagus (NE). Gene expression profiling with microarray and serial analysis of gene expression (SAGE) may help us understand the potential molecular mechanism of human BE.We analyzed three microarray datasets (two cDNA arrays and one oligonucleotide array) and one SAGE dataset with statistical tools, significance analysis of microarrays (SAM) and SAGE(Poisson), to identify individual genes differentially expressed in BE. Gene set enrichment analysis (GSEA) was used to identify a priori defined sets of genes that were differentially expressed. These gene sets were grouped according to either certain signaling pathways (GSEA curated), or the presence of consensus binding sequences of known transcription factors (GSEA motif). Immunohistochemical staining (IHC) was used to validate differential gene expression.Both SAM and SAGE(Poisson) identified 68 differentially expressed genes (55 BE genes and 13 NE genes) with an arbitrary cutoff ratio (> or =4-fold). With IHC on matched pairs of NE and BE tissues from 6 patients, these genes were grouped into 6 categories: category I (25 genes only expressed in BE), category II (5 genes only expressed in NE), category III (8 genes expressed more in BE than in NE), and category IV (2 genes expressed more in NE than in BE). Differential expression of the remaining genes was not confirmed by IHC either due to false discovery (category V), or lack of proper antibodies (category VI). Besides individual genes, the TGFbeta pathway and several transcription factors (CDX2, HNF1, and HNF4) were identified by GSEA as enriched pathways and motifs in BE. Apart from 9 target genes known to be up-regulated in BE, IHC staining confirmed up-regulation of 19 additional CDX1 and CDX2 target genes in BE.Our data suggested an important role of CDX1 and CDX2 in the development of BE. The IHC-confirmed gene list will lead to future studies on the molecular mechanism of BE.
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