ABSTRACT: Gene expression profiles of spontaneous gastric tumors in the antrum of the stomach of 30,60, and 90 day old CEA424-SV40 -T antigen transgenic mice.
Project description:This SuperSeries is composed of the following subset Series: GSE27710: Gene expression profiles of control GC424 tumor cell lines and after downregulation of the SV40 large T-antigen GSE27711: Gene expression profiles of spontaneous gastric tumors in the antrum of the stomach of 30,60, and 90 day old CEA424-SV40 -T antigen transgenic mice. Refer to individual Series
Project description:In this study, we characterized the transgenic mouse model of stomach adenocarcinoma CEA424-SV40 T Ag. Transgenic mice, generated in Prof Wolfgang Zimmermann’s lab (Ludwig-Maximilian University, Munich) (Tompson et al. Int J Cancer, 2000), produce spontaneous tumors in the pyloric region of the stomach in a time-dependent stage wise process. Combining multiple techniques, including transcriptomic analysis, we investigated the composition of the tumor microenvironment over time. We found that gastric tumors in CEA424-SV40 Tag present features of an immunosuppressive environment and are refractory to different immunotherapies. Comparing the expression profiles of tumors at early (day 60) and late stage (day80) we observed overexpression of stroma remodelling signatures, predicting poor overall survival in human patients of stomach adenocarcinoma. Finally, we demonstrated that combination of stroma-targeted T cell activation and PD-L1 inhibition potentiated CD8+ T cell migration to tumors. Our data demonstrate that the CEA424-SV40 T Ag model is clinically relevant and constitute an ideal platform to develop new immunotherapies, such as tumor-targeted stimulation of T cells combined with immune checkpoint blockade.
Project description:The role of microbe in promoting the initiation of gastric cancer (GC), the third most lethal cancer worldwide, are ill-defined. Here, we found that tumor size and weight in gp130F/F mouse stomach at condition were significantly reduced compared to those of at SPF condition. To investigate the underlying mechanism and how host genes were regulated in the presence/absence of microbe, arrays were performed in stomach tissue from gp130F/F and WT at 4 week old at SPF and GF conditions. The onset of gastric inflammation-associated adenomatous hyperplasia in gp130F/F mice occurs at ~6 weeks of age, with established intestinal-type tumors (3 months of age) progressively growing until a maximum size is reached at 6 months of age, with some evidence of carcinoma in situ. Since this phenotype histologically mimics early stage human GC, we therefore utilized gp130F/F mice as a model to identify miRNAs involved in the initiating molecular events leading to early stage GC. For this purpose, we performed miRNA microarrays on mouse gastric antrum tissue from gp130F/F and sex-matched littermate wild-type (gp130+/+) control mice aged 4 weeks; this age was chosen since antrum tissue from 4 week old (wo) gp130F/F mice is devoid of any histological signs of inflammation or hyperplasia, and is thus comparable to wild-type gastric antrum tissue.
Project description:We prepared miRNA from myofibroblats derived from normal stomach, both antrum (A) and corpus (C) separately and gastric cancers. miRCURYTM LNA Array ver5 was performed and comparisons were made by the dual (reference) method.
Project description:A small RNA library of stomach antrum tissue was sequenced using high-throughput SOLiD sequencing technology. The study aims to provide complementary information of the role of miRNAs in molecular regulation process in the healthy human stomach, in order to establish a reference for future comparisons of altered miRNA expression due to the gastric tract diseases.
Project description:Helicobacter pylori colonization of the human stomach is a strong risk factor for gastric cancer. To investigate H. pylori-induced gastric molecular alterations, we used a Mongolian gerbil model of gastric carcinogenesis. Histologic evaluation revealed varying levels of atrophic gastritis (a premalignant condition characterized by parietal and chief cell loss) in H. pylori-infected animals, and transcriptional profiling revealed a loss of markers for these cell types. We then assessed the spatial distribution and relative abundance of proteins in the gastric tissues using imaging mass spectrometry and liquid chromatography with tandem mass spectrometry (LC-MS/MS). We detected striking differences in protein content of corpus and antrum tissues. 492 proteins were preferentially localized to the corpus in uninfected animals. The abundance of 91 of these proteins was reduced in H. pylori-infected corpus tissues exhibiting atrophic gastritis compared to infected corpus tissues with non-atrophic gastritis or uninfected corpus tissues; these included numerous proteins with metabolic functions. Fifty proteins localized to the corpus in uninfected animals were diffusely delocalized throughout the stomach in infected tissues with atrophic gastritis; these included numerous proteins with roles in protein processing. Corresponding alterations were not detected in animals infected with a H. pylori ∆cagT mutant (lacking Cag type IV secretion system activity). These results indicate that H. pylori can cause loss of proteins normally localized to the gastric corpus as well as diffuse delocalization of corpus-specific proteins, resulting in marked changes in the normal gastric molecular partitioning into distinct corpus and antrum regions.
Project description:The glandular stomach is comprised of two anatomically and functionally distinct epithelial tissues termed corpus and antrum. While these compartments continuously regenerate to ensure normal organ function, our understanding of the molecular and cellular determinants that maintain these tissues remains incomplete. Here, we established an unbiased account of all gastric epithelial cells of the mouse corpus and antrum using single cell RNA-sequencing, allowing us to compare these adjacent epithelia and their stem cell compartments. Our data reveals that epithelial cell types with equivalent functional roles in the corpus and antrum utilize similar transcriptional programs, and our results support the existence of two discernible stem cell populations within the gland base and isthmus regions of these tissues. To study isthmus stem cells, typically underrepresented in conventional, gland base-enriched organoid cultures, we developed a novel 2D monolayer culture system to propagate mouse and human gastric epithelia. These 2D cultures expand indefinitely via Lgr5- isthmus-like cells and maintain the ability to differentiate into diverse gastric cell types. While 2D corpus and antrum cultures were transcriptionally similar, they retained a molecular memory and differentiation bias that mirrored their tissue of origin. Furthermore, gastric 2D cultures could be readily and reversibly converted into conventional 3D organoids, highlighting the remarkable plasticity of undifferentiated stomach epithelial cells. Finally, we utilized the 2D culture system to show that rare primary epithelial cells with high levels of Sox2 expression, previously hypothesized to be gastric stem cells, most closely resembled enterochromaffin (EC) cells and Sox2 is both necessary and sufficient to generate EC cells in vivo. Together, our data (i) provide important insights into the basis of gastric epithelial regeneration and differentiation, (ii) establish a tractable 2D culture system to capture and manipulate primary gastric isthmus stem cells in vitro and (iii) uncover a role for the stem cell factor Sox2 during EC cell specification.
Project description:The goal of this project was to compare the metabolite profiles of the: mouse gastric antrum and the mouse gastric corpus, the mouse gastric antrum and the mouse gastric antrum isolated glands, and the mouse gastric corpus and the mouse gastric corpus isolated glands.
Project description:Tissue-specific gene expression and gene regulation lead to a better understanding of tissue-specific physiology and pathophysiology. We analyzed the transcriptome and genetic regulatory profiles of two distinct gastric sites, corpus and antrum, to identify tissue-specific gene expression and its regulation. The transcriptome data from corpus and antral mucosa highlights the heterogeneity of gene expression in the stomach. We identified enriched pathways revealing distinct and common physiological processes in gastric corpus and antrum. Physiological differences are mostly related to digestion and epithelial protection. Furthermore, we found an enrichment of the single nucleotide polymorphism (SNP)-based heritability of metabolic, obesity-related, and cardiovascular traits and diseases by considering corpus- and antrum-specifically expressed genes. In particular, we could prioritize gastric-specific candidate genes for multiple metabolic traits, like NQO1 which is involved in glucose metabolism, MUC1 which contributes to purine and protein metabolism or RAB27B being a regulator of weight and body composition.