Next-generation sequencing analysis of molecular subtypes of gastric cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE180887 | GEO | 2021/07/29
REPOSITORIES: GEO
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Project description:Molecular knowledge of normal gastric tissues and gastric cancers remains incomplete. Here, we used single-cell RNA-seq to study the cell diversity of gastric tissues and gastric cancers. The expression landscape of normal gastric cell types and several candidate stem cell markers were obtained. Surprisingly, nearly all cell types in the antrum could transdifferentiate to intestinal metaplasia (IM). We also explored intra-tumoral heterogeneity and identified four common features of gastric cancer. In addition, we classified tumor cells into three major subtypes, which are associated with their prognosis. Finally, the proportions of mesenchymal and endothelial cells in the tumor microenvironment (TME) were negatively correlated with the prognosis of gastric cancer. Therefore, our work provides comprehensive molecular characterizations of both gastric development and gastric cancer at single-cell resolution and has significant potential to inspire better treatment strategies for gastric cancer. Keywords: Expression profiling by high throughput sequencing
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Project description:Background: Helicobacter pylori (HP) infection may initiate and promote progression of gastric carcinogenesis. ONECUT2 shows promise for tumor diagnosis, prognosis, and treatment. This study explored ONECUT2's role and specific mechanism underlying HP infection-associated gastric carcinogenesis to suggest a basis for targeting ONECUT2 as a therapeutic strategy for gastric cancer (GC). Methods: Public data, single-cell RNA sequencing, spatial transcriptome analysis, RNA sequencing, GC tissue specimens, and clinical survival data were analyzed. Human GC organoids, HP infection, 3D sphere-forming, and extreme-dilution nude mouse models were constructed. Western blotting, qPCR, immunohistochemical staining, dual-luciferase reporter assays, phosphokinase microarray, and immunofluorescence were used. Results: Multidimensional data supported an association between ONECUT2, HP infection, and GC pathogenesis. HP infection upregulated ONECUT2 transcriptional activity via NFκB. In vitro and in vivo experiments demonstrated that ONECUT2 increases stemness in GC cells. ONECUT2 was also shown to inhibit PPP2R4 transcription, resulting in reduced PP2A activity, which in turn increased AKT/β-catenin phosphorylation. AKT/β-catenin phosphorylation facilitates β-catenin translocation to the nucleus, initiating transcription of downstream stemness-associated genes in GC cell. HP infection could upregulate the phosphorylation of AKT and β-catenin triggered by ONECUT2 downregulation via induction of ONECUT2. Clinical survival analysis indicated that high ONECUT2 expression might be an indicator of poor prognosis in GC. Conclusion: This study highlights a critical role played by ONECUT2 in promoting HP infection-associated GC by enhancing cell stemness through the PPP2R4/AKT/β-catenin signaling pathway. These findings suggest promising therapeutic strategies and potential therapeutic targets for GC treatment. Keywords: Helicobacter pylori; gastric cancer; prognosis; tumor stemness; ONECUT2
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Project description:Understanding how the tumor microenvironment (TME) is orchestrated along the continuum of gastric adenocarcinoma (GAC) may uncover novel therapeutic strategies. Here, we performed comprehensive single-cell profiling of precancerous lesions, localized and metastatic GACs, identifying alterations in TME cell states and phenotypes during tumorigenesis and progression. IgA+ plasma cells appear to be the most active regulators in the premalignant microenvironment, whereas immunosuppressive myeloid and stromal subsets dominated the late-stage GACs. We discover six TME ecotypes, four of which are unique to the premalignant/progression in the continuum, with two ecotypes, identified in primary GACs, showing strong associations with histopathologic, genomic characteristics and prognosis. Extensive stromal remodeling is evident with GAC progression. High SDC2 expression in cancer-associated fibroblasts (CAFs) correlates with aggressive phenotypes and poor survival and SDC2 overexpression in CAFs contributes to tumor growth. This study illustrates a roadmap of the GAC TME and highlights potential targets for further investigation.
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Project description:Gastric cancer is the 3rd most lethal cancer worldwide, and the genomic status of its cancer cells has not translated into effective prognostic or therapeutic strategies. We therefore hypothesize that outcomes may depend on the tumor microenvironment (TME), and in particular cancer-associated fibroblasts (CAFs). However, very little is known about the role of CAFs in gastric cancer. To address this, we map the transcriptional landscape of human gastric cancer stroma by microdissection and RNA sequencing of CAFs from gastric cancer patients. We find a stromal gene signature associated with poor disease outcome. This signature is regulated by the transcription factor Heat Shock Factor 1 (HSF1), that activates CAF-derived extracellular vesicles (EVs) that transfer components including Inhibin Subunit Beta A (INHBA) and Thrombospondin 2 (THBS2), to the TME to promote cancer. Together, our work provides the first transcriptional map of human gastric cancer stroma, and highlights HSF1 and its transcriptional targets as potential diagnostic and therapeutic targets in the genomically stable tumor microenvironment.
2021-02-28 | GSE165211 | GEO
Project description:Gastric cancer is the 3rd most lethal cancer worldwide, and the genomic status of its cancer cells has not translated into effective prognostic or therapeutic strategies. We therefore hypothesize that outcomes may depend on the tumor microenvironment (TME), and in particular cancer-associated fibroblasts (CAFs). However, very little is known about the role of CAFs in gastric cancer. To address this, we map the transcriptional landscape of human gastric cancer stroma by microdissection and RNA sequencing of CAFs from gastric cancer patients. We find a stromal gene signature associated with poor disease outcome. This signature is regulated by the transcription factor Heat Shock Factor 1 (HSF1), that activates CAF-derived extracellular vesicles (EVs) that transfer components including Inhibin Subunit Beta A (INHBA) and Thrombospondin 2 (THBS2), to the TME to promote cancer. Together, our work provides the first transcriptional map of human gastric cancer stroma, and highlights HSF1 and its transcriptional targets as potential diagnostic and therapeutic targets in the genomically stable tumor microenvironment.
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Project description:Gastric cancer (GC) is a challenging malignant disease among gastrointestinal tumors. The clinical treatments for GC include surgery, neoadjuvant therapy and adjuvant chemotherapy. As patients’ response to chemotherapeutic drugs varies, an approach to predict the efficacy of chemotherapeutic treatment is urgently needed. Here, a biorepository of 17 human gastric tumor organoids (GTOs) and 9 normal organoids (GNOs) derived from GC patients was established, which contains the intestinal, diffuse and mixed-type of GC. GTOs retained morphologic, histopathological and genetic features of the tumors from which they were derived, and patient-derived organoid xenograft model indicated tumorigenicity of organoids. GTOs responses to clinically respective chemotherapy treatment positively correlated with the individual patient’s clinical response. Meanwhile, GNOs, which maintained original characteristics of corresponding tissues, could be separated from GTOs. The use of GNOs predicted the cytotoxic effect of chemotherapy on the organism. Our study implies that patient-derived organoids predict GC patient responses to chemotherapy and provide a solution for personalized treatment.
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Project description:In this study, we used single-cell RNA sequencing (scRNA-seq) to further elucidate the composition of the gastric cancer and adjacent normal tissue microenvironment and found that TNF and ACTG1 may be key regulators of regulatory T cells (Tregs) in gastric cancer. A total of seven cell types were identified, including B cells, T cells, NK cells, mast cells, fibroblasts, endothelial cells, and epithelial cells. T cells were further divided into 8 subgroups. Among them, Tregs showed the greatest difference between GC and adjacent normal tissues. Next, we clarified the function and signaling pathway of Tregs in the GC tumor microenvironment, obtained the key regulatory proteins TNF and ACTG1, and explored their clinical significance and possible effects on Tregs in the GC tumor microenvironment. This scRNA-seq study may reveal the composition of tumor microenvironment and clarify the role of Tregs in the development of gastric cancer, providing new methods for GC treatment.
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Project description:Gastric cancer (GC) is associated with high mortality rates and an unfavorable prognosis at advanced stages. In addition, there are no effective methods for diagnosing gastric cancer at an early stage or for predicting the outcome for the purpose of selecting patient-specific treatment options. Therefore, it is important to investigate new methods for GC diagnosis. We designed a custom microarray of gastric cancer. The customized microarray contained 1042 canceration and prognosis related genes identical to the probes on the Agilent microarray. DNA microarray profilling analysis was performed on gastric cancer tissues and premalignant tissues (20 samples per group).
2014-03-01 | E-MTAB-1881 | biostudies-arrayexpress
Project description:The better prognosis of patients with Epstein-Barr virus-positive gastric carcinoma than those with EBV-negative GC is correlated with the degree of recruitment of inflammatory tumor infiltrating cells (TIL) to the vicinity of tumor cells. We hypothesized that the better prognosis would associate with less genetic or epigenetic alterations in EBV(+)GC, or EBV infection should deregulate immune modulator proteins, of which secretion recruit TIL. Therefore we performed mRNA expression profilings in EBV(-)GC and EBV(+)GC, each of which was pair wise compared with their normal control. We found that EBV(+)GC had much more molecular homogeneity with focused alterations in immune modulator genes; The Pearson correlation matrix analyses demonstrated that EBV(+)GC tumor showed remarkably high tumor homogeneity. While EBV(-)GC had considerable number genes that are differentially expressed genes from their normal counterparts, EBV(+)GC showed only a handful, almost 20 fold less number of DEG than EBV(-)GC under the same p value cutoff (p<0.001). Gene ontology and pathway analyses showed that while pathways of cation homeostasis, digestion and ion transport were commonly deregulated in both GC types, genes for chromatin assembly, prostaglandin receptor activity, pattern specification process are selectively deregulated in EBV(-)GC tumors. In contrast, pathways or genes for cytokine activity, immune response and lipoprotein particle clearance are selectively deregulated in EBV(+)GC tumors. These results demonstrate that EBV(+)GC inherently evolves to high homogeneity with fewer changes in gene expression and these secret immune modulatory chemokines could recruit reactive immune cells to EBV(+)GC, leading to favorable microenvironment for cancer suppression. All patients underwent the surgery for advanced gastric carcinoma (GC) except one patient with early GC. The EBV-presence in the GC was verified by in situ EBV-encoded small RNA (ERER) staining.. The 14 paired EBV(-)GC patients and 12 paired EBV(+)GC patients were selected for this study. Tumor tissue (T)and normal tissues (N) from distant sites from tumor areas were dissected, frozen at -80C and were subjected to RNA purification, mRNA array profiling analyses.
2014-03-01 | E-GEOD-51575 | biostudies-arrayexpress