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Gastric squamous-columnar junction contains a large pool of cancer-prone immature osteopontin responsive Lgr5-CD44+ cells

ABSTRACT: We report the gene expression profiles of gastric squamous-columnar junction cancer derived from the mice with conditionally inactivation of Trp53 and Rb1 genes in Lgr5+ cells

ORGANISM(S): Mus musculus

PROVIDER: GSE130003 | GEO | 2020/01/13

REPOSITORIES: GEO

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Gastric squamous-columnar junction contains a large pool of cancer-prone immature osteopontin responsive Lgr5<sup>-</sup>CD44<sup>+</sup> cells.

Project description:Areas of a junction between two types of epithelia are known to be cancer-prone in many organ systems. However, mechanisms for preferential malignant transformation at the junction areas remain insufficiently elucidated. Here we report that inactivation of tumor suppressor genes Trp53 and Rb1 in the gastric squamous-columnar junction (SCJ) epithelium results in preferential formation of metastatic poorly differentiated neoplasms, which are similar to human gastroesophageal carcinoma. Unlike transformation-resistant antral cells, SCJ cells contain a highly proliferative pool of immature Lgr5-CD44+ cells, which are prone to transformation in organoid assays, comprise early dysplastic lesions, and constitute up to 30% of all neoplastic cells. CD44 ligand osteopontin (OPN) is preferentially expressed in and promotes organoid formation ability and transformation of the SCJ glandular epithelium. OPN and CD44 overexpression correlate with the worst prognosis of human gastroesophageal carcinoma. Thus, detection and selective targeting of the active OPN-CD44 pathway may have direct clinical relevance.

| S-EPMC6941991 | biostudies-literature

Gastric squamous-columnar junction contains a large pool of cancer-prone immature osteopontin responsive Lgr5-CD44+ cells

Project description:Gastric squamous-columnar junction contains a large pool of cancer-prone immature osteopontin responsive Lgr5-CD44+ cells

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Epithelial expressions of Gata4 and Sox2 regulate murine specification of the squamous–columnar junction via MAPK/ERK signaling

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

miRNAs high throughput sequencing profiling of basals cells and columnar cells

Project description:The airway mucociliary epithelium is consituted of three main cell types : columnar ciliated plus secretory cells and basal cells. Columnar cells are represented by a great majority of ciliated cells. We used Cell sorting by FACSaria to separate basal cells from ciliated and secreting columnar cells. Then, we performed microRNA high throughput sequencing to investigate the specific signature of microRNA of basal and columnar cells. miRNAs high throughput sequencing profiling of human nasal mucosa: basals cells (B) and columnars (C) cells for 3 donors.

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miRNAs high throughput sequencing profiling of basals cells and columnar cells

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Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche.

Project description:Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer deaths among women in the United States, but its pathogenesis is poorly understood. Some epithelial cancers are known to occur in transitional zones between two types of epithelium, whereas others have been shown to originate in epithelial tissue stem cells. The stem cell niche of the ovarian surface epithelium (OSE), which is ruptured and regenerates during ovulation, has not yet been defined unequivocally. Here we identify the hilum region of the mouse ovary, the transitional (or junction) area between the OSE, mesothelium and tubal (oviductal) epithelium, as a previously unrecognized stem cell niche of the OSE. We find that cells of the hilum OSE are cycling slowly and express stem and/or progenitor cell markers ALDH1, LGR5, LEF1, CD133 and CK6B. These cells display long-term stem cell properties ex vivo and in vivo, as shown by our serial sphere generation and long-term lineage-tracing assays. Importantly, the hilum cells show increased transformation potential after inactivation of tumour suppressor genes Trp53 and Rb1, whose pathways are altered frequently in the most aggressive and common type of human EOC, high-grade serous adenocarcinoma. Our study supports experimentally the idea that susceptibility of transitional zones to malignant transformation may be explained by the presence of stem cell niches in those areas. Identification of a stem cell niche for the OSE may have important implications for understanding EOC pathogenesis.

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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

A constant pool of Lgr5+ intestinal stem cells is required for intestinal homeostasis

Project description:Lgr5+ crypt base columnar cells, the operational intestinal stem cells (ISCs), are thought to be dispensable for small intestinal (SI) homeostasis. Using a novel Lgr5-2A-DTR (Diphtheria Toxin Receptor) model which ablates Lgr5+ cells with near-complete efficiency and retains endogenous levels of Lgr5 expression, we show that persistent depletion of Lgr5+ ISCs in fact compromises SI epithelial integrity and reduces epithelial turnover in vivo. In vitro, Lgr5-2A-DTR SI organoids are unable to establish or survive when Lgr5+ ISCs are continuously eliminated when DT is in the media. However, transient exposure to DT at the start of culture allows organoids to form, and the rate of outgrowth reduces with increasing length of DT presence. Our results indicate that intestinal homeostasis requires a constant pool of Lgr5+ ISCs, which is supplied by rapidly reprogrammed non-Lgr5+ crypt populations when pre-existing Lgr5+ ISCs are ablated.

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Single-cell RNA-seq characterization of columnar epithelial cells in mouse stomach.

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Analysis by RNA-seq of the transcriptional profile of three sub-populations of mouse colon epithelial cells (Lgr5+ columnar basal cells, goblet cells, enterocytes).

Project description:In this dataset, we report the analysis by RNA-sequencing (RNA-seq) of the transcriptional profile of three sub-populations of epithelial cells contained in the mouse colonic epithelium: 1) Epcam+/Cd44+/Kit-neg cells, which correspond to a population of epithelial cells located at the bottom of colonic crypts and enriched in Lgr5+ columnar basal cells (CBCs); 2) Epcam+/Cd44+/Kit+ cells, which correspond to a population of epithelial cells located at the bottom of colonic crypts and enriched in goblet cells; 3) Epcam+/Cd44-neg/Cd66-high cells, which correspond to a population of epithelial cells located at the top of colonic crypts and enriched in mature enterocytes (Rothenberg et al., Gastroenterology, 142:1195-1205, 2012).

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