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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 [scRNAseq]
| PRJNA883203 | ENA
Project description:Key Genetic Determinants Driving Esophageal Squamous Cell Carcinoma Initiation and Immune Evasion [bulkRNAseq]
| PRJNA882909 | ENA
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: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
Project description:Esophageal cancer (EC) has the seventh highest incidence and the sixth highest mortality rate of any type of cancer worldwide. In China, esophageal squamous cell carcinoma (ESCC) accounts for more than 95% of EC patients. The main treatment for EC patients is surgery and/or chemoradiotherapy (CRT). A large proportion of EC patients are already at an advanced stage of the disease by the time they are diagnosed. In these cases, CRT is left as the only treatment choice, and the treatment outcome is poor. Immune checkpoint inhibitors (ICIs) can improve clinical response and patient survival of patient with many types of tumors through reactivating antitumor immune response. The study of ICIs in ESCC is relative delayed compared with that in other solid tumors. Recent results from clinical trials have demonstrated the safety and efficacy of ICIs either alone or combined with chemotherapy or chemoradiotherapy in ESCC patients. Accumulated evidences also have shown the improved treatment outcome was associated with PD-L1 expression, tumor DNA instability-induced tumor mutational burden (TMB), and drawing lymphocytes into the tumor. Based on these findings, ICIs combined with CRT or radiotherapy (RT) are the focus of ongoing studies. This review will summarize the recent progress in this field, especially the mechanism of ICIs used in ESCC, their clinical efficacy and toxicities, and potential biomarkers.
| S-EPMC7576075 | biostudies-literature
Project description:Esophageal squamous cell carcinoma (ESCC) is one of the common malignant tumors in the world. More than half of patients with ESCC were detected in advanced or metastatic disease at the time of initial diagnosis and lost the opportunities of surgery. Currently, surgical resection, radiotherapy, and chemotherapy are most utilized in clinical practice, however, they are associated with limited survival benefits. Recognition of the limitation of traditional antitumor strategies prompt the development of new means to treat human cancer. In recent years, studies on immune checkpoint inhibitors (eg PD-1/PD-L1 inhibitors, CTLA-4 inhibitors, etc.) in ESCC have shown promising results. In addition, the combination of immune checkpoint inhibitor and traditional antitumor strategies for ESCC has caused extensive interest, and the results are encouraging. Previous analysis indicated that tumor cell PD-L1 expression, tumor mutation load (TMB), microsatellite instability-high status (MSI-H), and other biomarkers have relatively correlated with the efficacy of immunotherapy. This review explores the recent studies investigating checkpoint inhibitors in ESCC.
| S-EPMC6677374 | biostudies-literature