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Project description:Accumulated genetic mutations or copy number alterations are frequently observed in esophageal squamous cell carcinoma (ESCC) patients. However, it is still elusive which gene is the driver to initiate ESCC. We identified key genetic determinants for ESCC development using CRISPR/Cas9-based multiple genes KO mouse esophageal organoid model. Trp53, Cdkn2a, and Notch1 triple KO (PCN) organoid showed the phenotypes of ESCC. These triple genes KO served for cell proliferation through building multiple root cell clusters and remodeling the immune landscape beneficial for tumorigenesis by Ccl2-Ccr2 mediated intercellular interactions. Ccl2-releasing PCN tumors were surrounded by exhausted T cells and M2 macrophages leading to immune evasion. The PCN-type tumor was observed in more than 30% of ESCC patients who express high levels of B2M, CCL2, and NF-kB. Our study unveiled genetic determinants for ESCC development crucial for cell-autonomous growth as well as non-cell autonomous interactions with immune cells.
2023-06-07 | GSE213927 | GEO
Project description:Accumulated genetic mutations or copy number alterations are frequently observed in esophageal squamous cell carcinoma (ESCC) patients. However, it is still elusive which gene is the driver to initiate ESCC. We identified key genetic determinants for ESCC development using CRISPR/Cas9-based multiple genes KO mouse esophageal organoid model. Trp53, Cdkn2a, and Notch1 triple KO (PCN) organoid showed the phenotypes of ESCC. These triple genes KO served for cell proliferation through building multiple root cell clusters and remodeling the immune landscape beneficial for tumorigenesis by Ccl2-Ccr2 mediated intercellular interactions. Ccl2-releasing PCN tumors were surrounded by exhausted T cells and M2 macrophages leading to immune evasion. The PCN-type tumor was observed in more than 30% of ESCC patients who express high levels of B2M, CCL2, and NF-kB. Our study unveiled genetic determinants for ESCC development crucial for cell-autonomous growth as well as non-cell autonomous interactions with immune cells.
2023-06-07 | GSE213904 | GEO
Project description:Key Genetic Determinants Driving Esophageal Squamous Cell Carcinoma Initiation and Immune Evasion
| PRJNA883199 | ENA
Project description:Key Genetic Determinants Driving Esophageal Squamous Cell Carcinoma Initiation and Immune Evasion [bulkRNAseq]
| PRJNA882909 | ENA
Project description:Key Genetic Determinants Driving Esophageal Squamous Cell Carcinoma Initiation and Immune Evasion [scRNAseq]
| PRJNA883203 | ENA
Project description:Esophageal cancer (EC) is one of the most life-threatening malignancies worldwide. Esophageal squamous cell carcinoma (ESCC) is the dominant subtype, accounting for approximately 90% of new incident EC each year. Although multidisciplinary treatment strategies have advanced rapidly, patients with ESCC are often diagnosed at advanced stage and the long-term prognosis remains unsatisfactory. In recent decades, immunotherapy, such as immune checkpoint inhibitors (ICIs), tumor vaccines, and chimeric antigen receptor T-cell (CAR-T) therapy, has been successfully used in clinical practice as a novel therapy for treating tumors, bringing new hope to ESCC patients. However, only a small fraction of patients achieved clinical benefits due to primary or acquired resistance. Immune evasion plays a pivotal role in the initiation and progression of ESCC. Therefore, a thorough understanding of the mechanisms by which ESCC cells escape from anti-tumor immunity is necessary for a more effective multidisciplinary treatment strategy. It has been widely recognized that immune evasion is closely associated with the crosstalk between tumor cells and the tumor microenvironment (TME). TME is a dynamic complex and comprehensive system including not only cellular components but also non-cellular components, which influence hallmarks and fates of tumor cells from the outside. Novel immunotherapy targeting tumor-favorable TME represents a promising strategy to achieve better therapeutic responses for patients with ESCC. In this review, we provide an overview of immune evasion in ESCC, mainly focusing on the molecular mechanisms that underlie the role of TME in immune evasion of ESCC. In addition, we also discuss the challenges and opportunities of precision therapy for ESCC by targeting TME.
| S-EPMC9868934 | biostudies-literature
Project description: Not available
| S-EPMC5864622 | biostudies-literature
Project description:BackgroundEsophageal cancer (EC) is a common human malignancy worldwide. Esophageal squamous cell carcinoma (ESCC) is the predominant subtype in China. The tumorigenesis mechanism in ESCC is unclear. The aim of this study was to identify key transcription factors (TFs) in ESCC and elucidate the mechanism of it.MethodsA total of ten published microarray datasets of ESCC was downloaded from the Gene Expression Omnibus (GEO). Then, bioinformatics analyses including differentially expressed genes (DEGs) analysis, gene ontology (GO) annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, TFs-genes regulatory network construction was performed. Quantitative real-time polymerase chain reactions (qRT-PCR) were used to detect the expression levels of TFs and DEGs in ESCC. The association between stage and TFs and the association between survival and TFs were evaluated based on The Cancer Genome Atlas (TCGA), respectively.ResultsA total of 1,248 dysregulated genes were selected as DEGs in ESCC. A total of 26 TFs and corresponding target-genes were identified. The ESCC-specific transcriptional regulatory network was constructed. The network was consisted of 882 edges and 631 nodes. BRCA1, SOX10, ARID3A, ZNF354C and NFIC had the highest connectivity with DEGs, and regulated 92, 89, 82, 79 and 78 DEGs in the network, respectively. All these 1,248 DEGs were significantly enriched in cell cycle, DNA replication and oocyte meiosis pathways. The qRT-PCR results were consistent with our microarray analysis. High expression of SREBF1 and TFAP2A were significantly correlated with the longer overall survival time of patients with ESCC.ConclusionsBRCA1, SOX10, ARID3A, ZNF354C and NFIC might be the key TFs in carcinogenesis and development of ESCC by regulating their corresponding target-genes involved in cell cycle, DNA replication and oocyte meiosis pathways. SREBF1 and TFAP2A may be two potential prognostic biomarkers of ESCC.
| S-EPMC5863113 | biostudies-literature
Project description:BackgroundRadiotherapy plays an important effect on the standard therapy of esophageal squamous cell carcinoma (ESCC). However, the efficacy of the therapy is limited and a few patients do not achieve satisfactory treatment results due to the existence of radiation resistance. Therefore, it is necessary to identify the potential predictive biomarkers and treatment targets for ESCC.MethodsWe performed the whole-exome sequencing to determine the germline and somatic mutations in ESCC. Functional enrichment and pathway-based protein-protein interaction analyses were used to ascertain potential regulatory networks. Cell survival and cell death after treatment with radiotherapy were determined by CCK-8 and LDH release assays in ESCC cells. The correlations of NOTCH1 and tumor immune infiltration were also analyzed in ESCC.ResultsOur results showed that 344 somatic and 65 germline differentially mutated genes were detected to be radiosensitivity-related loci. The tumor mutational burdens (TMB) or microsatellite instability (MSI) were not significantly correlated with the response to radiotherapy in ESCC patients. Pathway-based protein-protein interaction analyses implied several hub genes with most nodes (such as PIK3CA, NOTCH1, STAT3 and KDR). The in vitro studies showed that the knockdown of NOTCH1 inhibited cell survival and rendered more cell death after the treatment with radiotherapy in ESCC cells, while NOTCH1 overexpression had the opposite effects. Moreover, NOTCH1, frequently up-regulated in ESCC, was negatively correlated with activated B cell and immature dendritic cell in ESCC. High expression of NOTCH1 was accompanied with the low levels of some immunotherapy-related cells, including CD8(+) T cells and NK cells.ConclusionsThese results indicate the differences of the germline mutations and somatic mutations between the radiosensitive and radioresistence groups in ESCC and imply that NOTCH1 plays important roles in regulating the radiosensitivity of ESCC. The findings might provide the biomarkers and potential treatment targets for improving the sensitivity to radiotherapy in ESCC.
| S-EPMC9478485 | biostudies-literature
Project description:Esophageal squamous cell carcinoma (ESCC) is the main prevalent histological type of esophageal cancer, predominantly constituting 90% of cases worldwide. Despite the development of multidisciplinary therapeutic approaches, its prognosis remains unfavorable. Recently, the development of monoclonal antibodies inhibiting programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1) has led to marked therapeutic responses among multiple malignancies including ESCC. However, only a few patients achieved clinical benefits due to resistance. Therefore, precise and accurate predictive biomarkers should be identified for personalized immunotherapy in clinical settings. Because the tumor immune microenvironment can potentially influence the patient's response to immune checkpoint inhibitors, tumor immunity, such as PD-L1 expression on tumors, tumor-infiltrating lymphocytes, tumor-associated macrophages, and myeloid-derived suppressor cells, in ESCC should be further investigated. In this review, accumulated evidence regarding the tumor immune microenvironment and immune checkpoint inhibitors in ESCC are summarized.
| S-EPMC7469863 | biostudies-literature