| Autor: |
Ho, Shamaine Wei Ting, Sheng, Taotao, Xing, Manjie, Ooi, Wen Fong, Xu, Chang, Sundar, Raghav, Huang, Kie Kyon, Li, Zhimei, Kumar, Vikrant, Ramnarayanan, Kalpana, Zhu, Feng, Srivastava, Supriya, Isa, Zul Fazreen Bin Adam, Anene-Nzelu, Chukwuemeka George, Razavi-Mohseni, Milad, Shigaki, Dustin, Ma, Haoran, Tan, Angie Lay Keng, Ong, Xuewen, Lee, Ming Hui, Tay, Su Ting, Guo, Yu Amanda, Huang, Weitai, Li, Shang, Beer, Michael A., Foo, Roger Sik Yin, Teh, Ming, Skanderup, Anders Jacobsen, Teh, Bin Tean, Tan, Patrick |
| Zdroj: |
Gut; 2023, Vol. 72 Issue: 2 p226-241, 16p |
| Abstrakt: |
ObjectiveGastric cancer (GC) comprises multiple molecular subtypes. Recent studies have highlighted mesenchymal-subtype GC (Mes-GC) as a clinically aggressive subtype with few treatment options. Combining multiple studies, we derived and applied a consensus Mes-GC classifier to define the Mes-GC enhancer landscape revealing disease vulnerabilities.DesignTranscriptomic profiles of ~1000 primary GCs and cell lines were analysed to derive a consensus Mes-GC classifier. Clinical and genomic associations were performed across >1200 patients with GC. Genome-wide epigenomic profiles (H3K27ac, H3K4me1 and assay for transposase-accessible chromatin with sequencing (ATAC-seq)) of 49 primary GCs and GC cell lines were generated to identify Mes-GC-specific enhancer landscapes. Upstream regulators and downstream targets of Mes-GC enhancers were interrogated using chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing, CRISPR/Cas9 editing, functional assays and pharmacological inhibition.ResultsWe identified and validated a 993-gene cancer-cell intrinsic Mes-GC classifier applicable to retrospective cohorts or prospective single samples. Multicohort analysis of Mes-GCs confirmed associations with poor patient survival, therapy resistance and few targetable genomic alterations. Analysis of enhancer profiles revealed a distinctive Mes-GC epigenomic landscape, with TEAD1as a master regulator of Mes-GC enhancers and Mes-GCs exhibiting preferential sensitivity to TEAD1 pharmacological inhibition. Analysis of Mes-GC super-enhancers also highlighted NUAK1kinase as a downstream target, with synergistic effects observed between NUAK1 inhibition and cisplatin treatment.ConclusionOur results establish a consensus Mes-GC classifier applicable to multiple transcriptomic scenarios. Mes-GCs exhibit a distinct epigenomic landscape, and TEAD1 inhibition and combinatorial NUAK1 inhibition/cisplatin may represent potential targetable options. |
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