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Key Genetic Determinants Driving Esophageal Squamous Cell Carcinoma Initiation and Immune Evasion [scRNAseq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE213927 | GEO | 2023/06/07

REPOSITORIES: GEO

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Key Genetic Determinants Driving Esophageal Squamous Cell Carcinoma Initiation and Immune Evasion [bulkRNAseq]

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

Identification of a methylome signature of esophageal squamous cell carcinoma

Project description:Background & Aims: Esophageal squamous cell carcinoma (ESCC) is believed to arise from esophageal mucosa through accumulation of both genetic and epigenetic changes. DNA methylation is a critical epigenetic mechanism involved in key cellular processes and its deregulation has been linked to many human cancers, including ESCC. The aim of this study is to examine the global deregulation of methylation states in ESCC and identify potential early biomarkers. Conclusions: This is the first study to address methylation changes in ESCC in a large panel of genes. Methylome analysis is shown as a sensitive and powerful tool to identify molecular players in ESCC. These data should prove to be the reference for future studies identifying potential biomarkers and molecular targets of ESCC. We performed a bead array analysis of more than 800 cancer-related genes in a series of 10 ESCC samples, 10 matched surrounding tissues, and 4 esophageal mucosa from healthy individuals. Pyrosequencing was used for validation of DNA methylation changes in up to 106 patients and 27 controls.

2011-11-23 | E-GEOD-26784 | biostudies-arrayexpress

A New Murine Esophageal Organoid Culture Method and Organoid-Driven Model of Esophageal Squamous Cell Neoplasia

Project description:We sought to develop esophageal minimum essential organoid culture medium (E-MEOM) for culturing murine esophageal organoids (EOs) and establishing an early ESCC model. We formulated E-MEOM that is sufficient to grow EOs from a single cell with clonal expansion, maintenance, and passage. From the IHC and single cell RNA sequencing of EOs results, we found that EOs cultured in E-MEOM were histologically and functionally equivalent to the esophageal epithelium.

2021-11-17 | GSE174577 | GEO

Differential protein expression between ESCC and normal tissues

Project description:To understand the difference of protein expression between paired esophageal squamous cell carcinoma (ESCC) and adjacent normal tissues, we collected 10 paired ESCC and normal tissues from surgical resected specimems for high-throughput proteomic experiments. From comparative analysis, the dysregulated signaling pathways in ESCC could be uncovered.

2020-08-11 | PXD019834 | Pride

Periostin cooperates with mutant p53 to mediate invasion

Project description:Periostin, a matricellular protein, has been reported to be important in supporting tumor cell dissemination. However, the molecular mechanisms underlying periostin function within the tumor microenvironment are poorly understood. In this study, we observe that loss of periostin decreases esophageal squamous cell carcinoma (ESCC) tumor growth in vivo and demonstrate that periostin cooperates with a conformational missense p53 mutation to enhance invasion. Pathway analyses reveal that invasive esophageal cells expressing periostin and p53R175H mutation display activation of signal transducer and activator of transcription 1 (STAT1) target genes, suggesting that the induction of STAT1 and STAT1-related genes could foster a permissive microenvironment that facilitates invasion of esophageal epithelial cells into the extracellular matrix (ECM). Genetic knockdown of STAT1 in transformed esophageal epithelial cells underscores the importance of STAT1 in promoting invasion and potentiate tumor resistance to genotoxic stress. Furthermore, we find that STAT1 is activated in ESCC xenograft tumors but this activation is attenuated with inducible knockdown of periostin in ESCC tumors. Overall, these results highlight the molecular mechanisms supporting the capacity of periostin in mediating tumor invasion during ESCC development. Pre-clinical study hTERT: EPC cells immortalized by expression of hTERT hTERT_p53: EPC cells expressing hTERT and mutant P53 hTERT_p53_POSTN: EPC cells expressing hTERT, mutant P53, and POSTN.

2016-06-01 | E-GEOD-48999 | biostudies-arrayexpress

Periostin, a cell adhesion molecule, facilitates invasion in the tumor microenvironment and annotates a novel tumor invasive signature in esophageal cancer

Project description:Human squamous cell cancers are the most common epithelially derived malignancies. One example is esophageal squamous cell carcinoma (ESCC), which is associated with a high mortality rate that is related to a propensity for invasion and metastasis. We report that periostin, a highly expressed cell adhesion molecule, is a key component of a novel tumor invasive signature obtained from an organotypic culture model of engineered ESCC. This tumor invasive signature classifies with human ESCC microarrays, underscoring its utility in human cancer. Genetic modulation of periostin promotes tumor cell migration and invasion as revealed in gain of and loss of function experiments. Inhibition of EGFR signaling and restoration of wild-type p53 function were each found to attenuate periostin, suggesting interdependence of two common genetic alterations with periostin function. Our studies reveal periostin as an important mediator of ESCC tumor invasion and they indicate that organotypic (3D) culture can offer an important tool to discover novel biologic effectors in cancer. Invading and non-invading genetically engineered human esophageal cells with hTERT and EGFR overexpression and p53 mutations were grown in organotypic culture. These invading and non-invading cells were excised using laser-capture microdissection. RNA was isolated and amplified for Affymetrix U133 microarrays. Subsequent microarray analysis & comparison with 2 independent cohorts of primary ESCC tumors revealed upregulation of periostin as gene with highest upregulation found in novel tumor invasive signature in esophageal cancer.

2010-07-08 | E-GEOD-21293 | biostudies-arrayexpress

Identification of a methylome signature of esophageal squamous cell carcinoma

2011-11-23 | GSE26784 | GEO

Spatial intratumor heterogeneity of epigenetic alterations in esophageal squamous cell carcinoma

Project description:Esophageal squamous cell carcinoma (ESCC) is among the most common malignancies, but little is known about the spatial intratumor heterogeneity (ITH) and the temporal clonal evolutionary processes in this cancer. Interestingly, the epigenetic profiling also showed strong evidence of spatial ITH, and the phyloepigenetic trees were extremely similar with the phylogenetic ones, indicating the interplay and co-dependency of genetic and epigenetic alterations in ESCC. We found that several genes were both mutated and hypermethylated at their promoters, such as ASXL1 and EPHA7. Our integrated investigations of the spatial ITH and the temporal clonal evolution might provide insights into developing biomarkers for early diagnosis of ESCC, as well as personalized therapeutic targets for treating this malignancy. DNA methylation profiles of 12 tumor regions and 2 matched normal esophageal epithelial tissues from three M-WES-examined ESCC cases (ESCC01, ESCC03 and ESCC05) were performed using Illumina Infinium HumanMethylation450K platform (Illumina, San Diego, CA) at the Epigenome Center of University of Southern California.

2016-08-20 | E-GEOD-79366 | biostudies-arrayexpress

African American esophageal squamous cell carcinoma expression profile reveals loss of detox networks

Project description:Esophageal carcinoma is the third most common gastrointestinal malignancy worldwide and is generally unresponsive to therapy. African Americans have an increased risk for esophageal squamous cell cancer (ESCC), the subtype that shows marked variation in geographic frequency. To identify key genes involved in ESC carcinogenesis in African Americans we conducted microarray expression profiling and found a significant dysregulation of genes encoding stress response and drug-metabolizing enzymes, mainly in NRF2 pathway. The involvement of NRF2 mediated oxidative damage represent a key step in the evolution of African American ESCC. Loss of activity of these enzymes would confer increased sensitivity of esophageal cells to xenobiotics, such as alcohol and tobacco smoke, and may account for the high incidence of ESCC in this ethnic group. The differential expression profile also indicates an inflammatory component and tissue regeneration in ESCC tumorigenesis. Together, these findings suggest a remarkable interplay of genetic and environmental factors in the pathogenesis of African American ESCC.

2017-08-15 | GSE77861 | GEO

a-CGH of Esophageal Cancer (70 cases)

Project description:Esophageal cancer is one of the most aggressive cancers and the sixth leading cause of cancer death worldwide. Approximately 70% of the global esophageal cancers occur in China and over 90% histopathological forms of this disease are esophageal squamous cell carcinoma (ESCC). Currently, there are limited clinical approaches for early diagnosis and treatment for ESCC, resulting in a 10% 5-year survival rate for the patients. Meanwhile, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we show a comprehensive genomic analysis in 158 ESCC cases, as part of the International Cancer Genome Consortium (ICGC) Research Projects (http://icgc.org/icgc/cgp/72/371/1001734). We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases and additional 70 ESCC cases were subjected to array comparative genomic hybridization (a-CGH) analysis. We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases and additional 70 ESCC cases were subjected to array comparative genomic hybridization (a-CGH) analysis.

2014-03-11 | E-GEOD-54993 | biostudies-arrayexpress

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