Parallel single cell and bulk transcriptome analyses reveal key features of the gastric tumor microenvironment
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ABSTRACT:
PROVIDER: PRJNA852186 | ENA |
REPOSITORIES: ENA
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Project description:We used single-cell RNA-sequencing from tumors and matched normal tissue of 24 treatment-naïve patients to generate a single cell landscape of gastric cancer tumor microenvironment.
2022-09-30 | GSE206785 | GEO
Project description:BackgroundThe tumor microenvironment (TME) has been shown to strongly influence treatment outcome for cancer patients in various indications and to influence the overall survival. However, the cells forming the TME in gastric cancer have not been extensively characterized.ResultsWe combine bulk and single-cell RNA sequencing from tumors and matched normal tissue of 24 treatment-naïve GC patients to better understand which cell types and transcriptional programs are associated with malignant transformation of the stomach. Clustering 96,623 cells of non-epithelial origin reveals 81 well-defined TME cell types. We find that activated fibroblasts and endothelial cells are most prominently overrepresented in tumors. Intercellular network reconstruction and survival analysis of an independent cohort imply the importance of these cell types together with immunosuppressive myeloid cell subsets and regulatory T cells in establishing an immunosuppressive microenvironment that correlates with worsened prognosis and lack of response in anti-PD1-treated patients. In contrast, we find a subset of IFNγ activated T cells and HLA-II expressing macrophages that are linked to treatment response and increased overall survival.ConclusionsOur gastric cancer single-cell TME compendium together with the matched bulk transcriptome data provides a unique resource for the identification of new potential biomarkers for patient stratification. This study helps further to elucidate the mechanism of gastric cancer and provides insights for therapy.
| S-EPMC9773611 | biostudies-literature
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
2022-09-27 | GSE112302 | GEO
Project description:Metastatic gastric carcinoma is a highly lethal cancer that responds poorly to conventional and molecularly targeted therapies. Despite its clinical relevance, the mechanisms underlying the behavior and therapeutic response of this disease are poorly understood owing, in part, to a paucity of tractable models that faithfully recapitulate different subtypes of the human disease. To close this gap, we developed methods to somatically introduce different oncogenic lesions directly into the stomach epithelium and show that genotypic configurations observed in patients produce metastatic gastric cancers that recapitulate the histological, molecular, and clinical features of all non-viral molecular subtypes of the human disease. Applying this platform to both wild-type and immune-deficient mice revealed previously unappreciated links between the genotype, organotropism and immune surveillance of metastatic cells that produced distinct patterns of metastasis that were mirrored in patients. Our results establish and credential a highly portable platform for producing autochthonous cancer models with flexible genotypes and host backgrounds, which can unravel mechanisms of gastric tumorigenesis or test new therapeutic concepts aimed at improving outcomes in gastric cancer patients.
2023-09-03 | GSE199261 | GEO
Project description:Signet ring cell carcinoma (SRCC) is a histological subtype of gastric cancer with distinct features in multiple aspects compared to adenocarcinomas (ACs). Lacking of systematically molecular overview to this disease made a slow progress in its clinical practice. In the present proteomics study, gastric tissues were collected from tumor and adjacency including 14 SRCCs and 34 ACs, and laser capture microdissection (LCM) was employed to eradicate cellular heterogeneity of the tissues. Proteome of tissues were profiled by data independent acquisition (DIA) mass spectrometry (MS). Based on the over 6 000 proteins quantified. Univariate analysis and pathway enrichment revealed that some proteins and pathways bared the differences between SRCC and ACs. Importantly, the up regulation for a majority of complement-related proteins were iconic for SRCC but not for AC. A hypothesis, based on the proteomics evidence, was proposed that the complement cascade was evoked in the SRCC microenvironment upon infiltration, while the SRCC cells survived the complement cytotoxicity by secreting endogenous negative regulators. Moreover, an attempt was made to seek appropriate cell models for gastric SRCC, through proteomic comparison of the 15 gastric cell lines and the gastric tumors. The prediction of supervised classifier suggested none of these gastric cell lines qualified in mimicking SRCC. This study discovered that complement cascade is activated at a higher level in gastric SRCC than AC.
2021-02-25 | PXD022405 | Pride
Project description:Signet ring cell carcinoma (SRCC) is a histological subtype of gastric cancer with distinct features in multiple aspects compared to adenocarcinomas (ACs). Lacking of systematically molecular overview to this disease made a slow progress in its clinical practice. In the present proteomics study, gastric tissues were collected from tumor and adjacency including 14 SRCCs and 34 ACs, and laser capture microdissection (LCM) was employed to eradicate cellular heterogeneity of the tissues. Proteome of tissues were profiled by data independent acquisition (DIA) mass spectrometry (MS). Based on the over 6 000 proteins quantified. Univariate analysis and pathway enrichment revealed that some proteins and pathways bared the differences between SRCC and ACs. Importantly, the up regulation for a majority of complement-related proteins were iconic for SRCC but not for AC. A hypothesis, based on the proteomics evidence, was proposed that the complement cascade was evoked in the SRCC microenvironment upon infiltration, while the SRCC cells survived the complement cytotoxicity by secreting endogenous negative regulators. Moreover, an attempt was made to seek appropriate cell models for gastric SRCC, through proteomic comparison of the 15 gastric cell lines and the gastric tumors. The prediction of supervised classifier suggested none of these gastric cell lines qualified in mimicking SRCC. This study discovered that complement cascade is activated at a higher level in gastric SRCC than AC.
2021-02-25 | PXD022627 | Pride
Project description:Signet ring cell carcinoma (SRCC) is a histological subtype of gastric cancer with distinct features in multiple aspects compared to adenocarcinomas (ACs). Lacking of systematically molecular overview to this disease made a slow progress in its clinical practice. In the present proteomics study, gastric tissues were collected from tumor and adjacency including 14 SRCCs and 34 ACs, and laser capture microdissection (LCM) was employed to eradicate cellular heterogeneity of the tissues. Proteome of tissues were profiled by data independent acquisition (DIA) mass spectrometry (MS). Based on the over 6 000 proteins quantified. Univariate analysis and pathway enrichment revealed that some proteins and pathways bared the differences between SRCC and ACs. Importantly, the up regulation for a majority of complement-related proteins were iconic for SRCC but not for AC. A hypothesis, based on the proteomics evidence, was proposed that the complement cascade was evoked in the SRCC microenvironment upon infiltration, while the SRCC cells survived the complement cytotoxicity by secreting endogenous negative regulators. Moreover, an attempt was made to seek appropriate cell models for gastric SRCC, through proteomic comparison of the 15 gastric cell lines and the gastric tumors. The prediction of supervised classifier suggested none of these gastric cell lines qualified in mimicking SRCC. This study discovered that complement cascade is activated at a higher level in gastric SRCC than AC.
2021-02-25 | PXD022952 | Pride
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Project description:Differential Impacts of CD8+ T-cells landscapes on Gastric Cancer Immune Microenvironment
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Project description:FoxL1+telocytes (TCFoxL1+) are novel gastrointestinal subepithelial cells that form communication axis between the mesenchyme and epithelium. TCFoxL1+ are strategically positioned to be key contributors to the microenvironment through production and secretion of growth factors and extracellular matrix (ECM) proteins. In recent years, the alteration of the bone morphogenetic protein (BMP) signaling in TCFoxL1+ was demonstrated to trigger a toxic microenvironment with ECM remodeling that leads to the development of pre-neoplastic gastric lesions. However, a comprehensive analysis of variations in the ECM composition and its associated proteins in gas-tric neoplasia linked to TCFoxL1+ dysregulation has never been performed. This study provides a better understanding of how TCFoxL1+ defective BMP signaling participates in gastric pre-neoplastic microenvironment. Using a proteomic approach, we determined the changes in the complete matrisome of BmpR1a△FoxL1+ and control mice, both in total antrum as well as in isolated mesenchyme-enriched antrum fractions. Comparative proteomic analysis revealed that the deconstruction of the gastric antrum led to a more comprehensive analysis of the ECM frac-tion of gastric tissues microenvironment. These results show that TCFoxL1+ are key members of the mesenchymal cell population and actively participate in the establishment of the matrisomic fraction of the microenvironment; thus, influencing epithelial cell behavior
2023-03-11 | PXD038603 | Pride