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Eosinophils exert direct and indirect anti-tumorigenic effects in the development of esophageal squamous cell carcinoma [eos]

ABSTRACT: Eosinophils are present in several solid tumors and have context-dependent function. The role of eosinophils in the development of esophageal squamous cell cancer (ESCC), 85% of esophageal cancers worldwide, is unknown. Mice were treated with 4-nitroquinolone-1-oxide (4-NQO) for 8 weeks followed by vehicle for 8 weeks to induce esophageal squamous pre-cancer. Eosinophil depletion using three mouse models resulted in exacerbated 4-NQO tumorigenesis. In order to study the transcriptional profiles of eosinophils specifically, we isolated eosinophils from esophageal tissue of WT mice which had been treated with 4-NQO in the pre-cancer model. Because eosinophils are not present in the esophagus normally, we isolated eosinophils from the colons of a random subset of the same mice. Additionally, we derived eosinophils from the bone marrow of a random subset of the same mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE233448 | GEO | 2023/12/01

REPOSITORIES: GEO

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Project description:Esophageal cancer is one of the most common cancers where TP53 is mutated frequently. Esophageal squamous cell carcinoma (ESCC) is the major subtype of esophageal cancer, and is one of the most lethal cancers worldwide. ESCC evolves often to lung metastasis, which is associated with a dismal prognosis. P53R175H (homologous to Trp53R172H in mice) is a common hot spot mutation. How metastasis is regulated by p53R175H in ESCC, or cancers in general, remains to be elucidated. To investigate p53R175H mediated molecular mechanisms, we utilized germline Trp53R172H/- mice, and generated esophageal specific Trp53-/- mice and Trp53+/+ mice treated with the 4-NQO esophageal-specific carcinogen (a common exposure in humans) to model ESCC. In the primary Trp53R172H/- tumor cell lines established from these mouse models, we depleted Trp53R172H (shTrp53) and observed a marked reduction in cell invasion in vitro and lung metastasis burden in a tail-vein injection model in comparing isogenic cells (shCtrl). Furthermore, to understand the molecular basis for mutant p53 driven lung metastasis, we performed bulk RNA-seq to compare gene expression profiles of metastatic and primary shCtrl and shTrp53 cells. We performed Gene Set Enrichment Analysis (GSEA) and identified the YAP-BIRC5 axis as a potential mediator of Trp53R172H mediated metastasis. As a target gene of YAP, BIRC5 encodes an anti-apoptotic protein, namely survivin. We demonstrate that survivin expression increases in the presence of Trp53R172H but not wild-type Trp53. Furthermore, depletion of survivin decreases Trp53R172H driven lung metastasis. Mechanistically, Trp53R172H but not wild-type Trp53, binds with YAP in ESCC cells, suggesting their cooperation to induce survivin expression. Furthermore, survivin high expression level is associated with increased metastasis in several GI cancer, suggesting that survivin may be a key regulator to metastasis. Taken together, this study unravels new insights into how mutant p53 mediates metastasis.

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Eosinophils exert direct and indirect anti-tumorigenic effects in the development of esophageal squamous cell carcinoma [eos]

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