Objective Genomic studies of gastric cancer have identified highly recurrent genomic alterations impacting RHO signalling, especially in the diffuse gastric cancer (DGC) histological subtype. Among these alterations are interchromosomal translations leading to the fusion of the adhesion protein CLDN18 and RHO regulator ARHGAP26. It remains unclear how these fusion constructs impact the activity of the RHO pathway and what is their broader impact on gastric cancer development. Herein, we developed a model to allow us to study the function of this fusion protein in the pathogenesis of DGC and to identify potential therapeutic targets for DGC tumours with these alterations. Design We built a transgenic mouse model with LSL-CLDN18-ARHGAP26 fusion engineered into the Col1A1 locus where its expression can be induced by Cre recombinase. Using organoids generated from this model, we evaluated its oncogenic activity and the biochemical effects of the fusion protein on the RHOA pathway and its downstream cell biological effects in the pathogenesis of DGC. Results We demonstrated that induction of CLDN18-ARHGAP26 expression in gastric organoids induced the formation of signet ring cells, characteristic features of DGC and was able to cooperatively transform gastric cells when combined with the loss of the tumour suppressor gene Trp53. CLDN18-ARHGAP26 promotes the activation of RHOA and downstream effector signalling. Molecularly, the fusion promotes activation of the focal adhesion kinase (FAK) and induction of the YAP pathway. A combination of FAK and YAP/TEAD inhibition can significantly block tumour growth. Conclusion These results indicate that the CLDN18-ARHGAP26 fusion is a gain-of-function DGC oncogene that leads to activation of RHOA and activation of FAK and YAP signalling. These results argue for further evaluation of emerging FAK and YAP-TEAD inhibitors for these deadly cancers. All data relevant to the study are included in the article or uploaded as supplementary information.

中文翻译：

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复发性 RhoGAP 基因融合 CLDN18-ARHGAP26 促进弥漫性胃癌中 RHOA 激活、粘着斑激酶和 YAP-TEAD 信号传导

目的 胃癌的基因组研究已经确定了影响 RHO 信号传导的高度重复的基因组改变，特别是在弥漫性胃癌 (DGC) 组织学亚型中。这些改变包括导致粘附蛋白 CLDN18 和 RHO 调节因子 ARHGAP26 融合的染色体间翻译。目前尚不清楚这些融合构建体如何影响 RHO 通路的活性以及它们对胃癌发展的更广泛影响。在此，我们开发了一个模型，使我们能够研究这种融合蛋白在 DGC 发病机制中的功能，并确定具有这些改变的 DGC 肿瘤的潜在治疗靶点。设计 我们建立了一个转基因小鼠模型，将 LSL-CLDN18-ARHGAP26 融合基因工程改造到 Col1A1 基因座中，在该基因座中，Cre 重组酶可以诱导其表达。使用从该模型生成的类器官，我们评估了其致癌活性和融合蛋白对 RHOA 途径的生化作用及其在 DGC 发病机制中的下游细胞生物学效应。结果我们证明，在胃类器官中诱导 CLDN18-ARHGAP26 表达可诱导印戒细胞的形成，这是 DGC 的特征，并且当与抑癌基因 Trp53 的缺失相结合时，能够协同转化胃细胞。 CLDN18-ARHGAP26 促进 RHOA 和下游效应信号的激活。从分子角度来看，融合促进了粘着斑激酶 (FAK) 的激活和 YAP 通路的诱导。 FAK 和 YAP/TEAD 抑制的组合可以显着阻止肿瘤生长。结论 这些结果表明 CLDN18-ARHGAP26 融合体是一种功能获得性 DGC 癌基因，可导致 RHOA 激活以及 FAK 和 YAP 信号传导激活。这些结果支持对新兴的 FAK 和 YAP-TEAD 抑制剂针对这些致命癌症的进一步评估。与研究相关的所有数据都包含在文章中或作为补充信息上传。