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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.

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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.

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