Modeling, dissecting, and subtyping of E-cadherin inactivation-associated diffuse-type gastric adenocarcinoma
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ABSTRACT:
PROVIDER: PRJNA939274 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23635576.fastq.gz | Fastqsanger.gz | |||
| SRR23635577.fastq.gz | Fastqsanger.gz | |||
| SRR23635578.fastq.gz | Fastqsanger.gz |
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Project description:Diffuse-type gastric adenocarcinoma (DGAC) is lethal cancer that is often diagnosed late and resistant to therapeutics. Although hereditary DGAC is mainly characterized by mutations in the CDH1 gene that encodes E-cadherin, the impact of E-cadherin inactivation in DGAC tumorigenesis remains unclear. To address this, we established and characterized a CDH1 loss-associated DGAC model system with a human DGAC single-cell transcriptome. We genetically engineered murine gastric organoids (GOs; Cdh1 KO, KrasG12D, Trp53 KO [EKP]) that recapitulates human DGAC tumorigenesis. Cdh1 depletion is sufficient to 1. Single-cell transcriptomics of human DGAC datasets classified patients into three subtypes (DGAC1, 2, and 3). By transcriptional signature, EKP GOs belong to the DGAC1 subtype displaying CDH1 downregulation and epithelial-mesenchymal transition. Compared to DGAC2 and DGAC3, the DGAC1 subtype was characterized by T cell exhaustion, PILRA-CD99 enrichment, and potential sensitivity to PD1 inhibitors. Additionally, we identified the EZH2-mediated transcriptional circuit as a key regulon specifically activated in EKP and a therapeutic vulnerability. This study unravels the unexpected role of E-cadherin loss in cell lineage plasticity, transcriptional reprogramming, and immune evasion of DGAC and further stratifies DGAC patients by single-cell transcriptomics, providing novel insights into E-cadherin loss-associated DGAC tumorigenesis.
2023-08-07 | GSE226266 | GEO
Project description:BACKGROUND & AIMS: Gastric cancer is the second most frequent cause of death from cancer in the world, diffuse-type gastric cancer (DGC) exhibiting a poor prognosis. Germline mutations of CDH1, encoding E-cadherin, have been reported in hereditary DGCs, and genetic and/or epigenetic alterations of CDH1 are frequently detected in sporadic DGCs. Genetic alterations of TP53 are also frequently found in DGCs. To examine the synergistic effect of loss of E-cadherin and p53 on gastric carcinogenesis, we established a mouse line in which E-cadherin and p53 are specifically inactivated in the stomach parietal cell lineage. METHODS: We crossed Atp4b-Cre mice with Cdh1loxP/loxP and Trp53loxP/loxP mice, and examined the gastric phenotype of Atp4b-Cre+;Cdh1loxP/loxP;Trp53loxP/loxP mice. RESULTS: Non-polarization of E-cadherin-negative parietal cells and proton pump-negative atypical foci were observed in the transgenic mice. Intramucosal cancers and invasive cancers composed of poorly differentiated carcinoma cells and signet ring cells, which were histologically very similar to those in humans, were found from 6 and 9 months, respectively. Fatal DGCs developed at 100% penetrance within a year, frequently metastasized to lymph nodes, and had tumorigenic activity in immunodeficient mice. Gene expression profiling analyses also revealed that DGCs in the E-cadherin/p53-deficient mice resembled human DGCs. CONCLUSIONS: Our mouse line is the first genetically modified mouse model of DGC and very useful for clarifying the mechanism underlying gastric carcinogenesis, and provides a new approach to the treatment and prevention of DGC because of morphological and biochemical similarities with human DGC. Two-condition experiment, Gastric cancer vs. normal gastric mucosal tissues. Biological replicates: pooled control sample from five normal gastric mucosal tissues, three replicates from diffuse-type gastric cancer.
2011-12-04 | E-GEOD-25302 | biostudies-arrayexpress
Project description:BACKGROUND & AIMS: Gastric cancer is the second most frequent cause of death from cancer in the world, diffuse-type gastric cancer (DGC) exhibiting a poor prognosis. Germline mutations of CDH1, encoding E-cadherin, have been reported in hereditary DGCs, and genetic and/or epigenetic alterations of CDH1 are frequently detected in sporadic DGCs. Genetic alterations of TP53 are also frequently found in DGCs. To examine the synergistic effect of loss of E-cadherin and p53 on gastric carcinogenesis, we established a mouse line in which E-cadherin and p53 are specifically inactivated in the stomach parietal cell lineage. METHODS: We crossed Atp4b-Cre mice with Cdh1loxP/loxP and Trp53loxP/loxP mice, and examined the gastric phenotype of Atp4b-Cre+;Cdh1loxP/loxP;Trp53loxP/loxP mice. RESULTS: Non-polarization of E-cadherin-negative parietal cells and proton pump-negative atypical foci were observed in the transgenic mice. Intramucosal cancers and invasive cancers composed of poorly differentiated carcinoma cells and signet ring cells, which were histologically very similar to those in humans, were found from 6 and 9 months, respectively. Fatal DGCs developed at 100% penetrance within a year, frequently metastasized to lymph nodes, and had tumorigenic activity in immunodeficient mice. Gene expression profiling analyses also revealed that DGCs in the E-cadherin/p53-deficient mice resembled human DGCs. CONCLUSIONS: Our mouse line is the first genetically modified mouse model of DGC and very useful for clarifying the mechanism underlying gastric carcinogenesis, and provides a new approach to the treatment and prevention of DGC because of morphological and biochemical similarities with human DGC.
2011-12-04 | GSE25302 | GEO
Project description:Breast cancer was one of the first cancer types where molecular subtyping led to explanation of interpersonal heterogeneity and resulted in improvement of treatment regimen. Several multigene classifiers have been developed and in particular those defining molecular signatures of early breast cancers possess significant prognostic information. Hence since 2014, molecular subtyping of primary breast cancers was implemented as a part of routine diagnostics with direct impact of therapy assignment. In this study, we evaluate direct and potential benefits of molecular subtyping in low-risk breast cancers as well as present the advantages of a robust molecular signature in regard to patient work-up among high-risk breast cancers.
2017-12-01 | E-MTAB-5724 | biostudies-arrayexpress
Project description:Diffuse-type gastric cancer (DGC) exhibits rapid disease progression and a poor patient prognosis. We have previously established an E-cadherin/p53 double conditional knockout (DCKO) mouse line as the first genetically engineered one, which morphologically and molecularly recapitulates human DGC. In this study, we explored low-molecular-weight drugs selectively eliminating mouse DGC cells, and then validated their inhibitory effects on human DGC. We first derived mouse gastric cancer (GC) cell lines from DGC of the DCKO mice, which notably demonstrated enhanced tumorigenic activity in immunodeficient mice and acquired tolerance to cytotoxic anti-cancer agents. We next performed a synthetic lethal screening of 1535 annotated chemical compounds by using them. Comparing cell viability of the E-cadherin/p53-deficient GC and p53-deficient gastric epithelial (GE) cells under treatment with the compound library, we identified 27 candidates with specific toxicity to the GC cell lines. The most potent drug mestranol, an estrogen derivative, and other estrogen receptor modulators induced apoptotic events preceded by DNA damage only in the GC cell lines, but not in the GE. Moreover, mestranol could significantly suppress tumor growth of the GC cells subcutaneously transplanted into nude mice, consistent with longer survival time in the female DCKO mice than in the male. As expected, human E-cadherin-mutant and -low gastric cancer cells showed higher susceptibility to estrogen drugs in contrast to E-cadherin-intact ones in vitro and in vivo. These findings may lead to the development of novel therapeutic strategies targeting E-cadherin-deficient DGC.
2018-07-31 | GSE102297 | GEO
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2018-12-19 | GSE108317 | GEO
Project description:We conditionally substituted E-cadherin (E-cad; cadherin 1) with N-cadherin (N-cad; cadherin 2) during intestine development by generating mice in which an Ncad cDNA was knocked into the Ecad locus We used microarray to follow gene expression changes derived from lack of E-cadherin on intestinal epithelial cells
2017-05-01 | GSE81920 | GEO
Project description:The aim of the experiment was to compare a newly defined population VE-Cadherin+GFP+ to control populations, VE-Cadherin- GFP+ and VE-Cadherin+GFP-.
2019-04-20 | GSE113403 | GEO
Project description:Objection: To evaluate a qPCR-based 32-gene expression assay to determine the cell-of-origin (COO) of diffuse large B-cell lymphoma (DLBCL) with formalin-fixed paraffin-embedded (FFPE) tissue. Methods: The most established subtyping algorithm, the COO model, categorizes DLBCL into activated B-cell (ABC) and germinal center B-cell (GCB)-like subgroups through gene expression profiling. Biopsy of DLBCL patients with paired FFPE and fresh frozen tissue were collected to assign COO based on the immunohistochemistry (IHC) algorithm (Han’s algorithm), qPCR-based 32-gene expression assay (DLBCL-COO assay) and global gene expression profiling with RNA-seq. Results: The DLBCL-COO assay demonstrated a significantly superior concordance of COO determination with the “gold standard” RNA-seq, comparing with the IHC assignment with Han’s algorithm (91.9% versus 77.5%; P = 0.005). Furthermore, overall survival of GCB patients defined by DLBCL-COO assay was superior significantly towards the ABC patients (Figure 2B, P = 0.023). This effect was not seen when tumors were classified by IHC algorithm. Conclusions: The DLBCL-COO assay provides flexibility and accuracy in DLBCL subtype characterization. These subtype distinctions should help guiding prognostic and therapeutic options for the patients in our daily practice.
2020-04-22 | GSE147986 | GEO
Project description:The Keratin 17/YAP/IL6 Axis contributes to E-cadherin Loss and Aggressiveness of Diffuse Gastric Cancer
| PRJNA721315 | ENA