CLDN18-ARHGAP26 fusion promotes RHOA activation and focal adhesion kinase and YAP-TEAD signalling in diffuse gastric cancer

Sep 21, 2026

Upload by Liam

Objective: Genomic studies in gastric cancer highlight recurrent alterations affecting RHO signalling, particularly in the diffuse gastric cancer (DGC) subtype. A key event is interchromosomal translation producing the CLDN18–ARHGAP26 fusion, whose mechanism and contribution to DGC progression remain uncertain. Methods: A transgenic mouse model with LSL-CLDN18–ARHGAP26 at the Col1A1 locus, plus organoid analyses, assessed oncogenic function and downstream biochemical and cellular effects. Results: Fusion induction generated signet ring cells and cooperatively transformed cells with Trp53 loss, activating RHOA, FAK, and YAP pathway signalling. Conclusion: CLDN18–ARHGAP26 acts as a gain-of-function DGC oncogene, supporting evaluation of FAK and YAP-TEAD inhibitors.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

ABSTRACT

Objective

Design

Results

Conclusion

INTRODUCTION

Gastric cancer background

Key molecular features of DGC

Stomach Original research Recurrent RhoGAP gene fusion CLDN18-ARHGAP26 promotes RHOA activation and focal adhesion kinaseand YAP-TEAD signalling in diffuse gastric cancer Feifei Zhang, 1,2 Varun Sahu,3,4 Ke Peng,2,5 Yichen Wang,2,6 Tianxia Li,3 Pratyusha Bala,2 Daulet Aitymbayev,2 Pranshu Sahgal ,2 Antje Schaefer,7,8 Channing J Der,8,9 Sandra Ryeom, 10 Sam Yoon, 10 Nilay Sethi ,2 Adam J Bass,3,11 Haisheng Zhang 1,2,12 ► Additional supplemental material is published online only. To view, please visit the journal online ([https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.1136/gutjnl-2023-329686](10.1136/gutjnl-2023-329686)) . For numbered affiliations see end of article. Correspondence to Dr Haisheng Zhang, 1838 Guangzhou Blvd N, Baiyun, Guangzhou, Guangdong Province, China; eslite3000@gmail.com and Dr Adam J Bass, 1130 St Nicholas Avenue, New York, NY 10032, USA; [ab5147@cumc.columbia.edu](ab5147@cumc.columbia.edu) FZ and VS contributed equally. AJB and HZ contributed equally. Received 10 February 2023 Accepted 8 February 2024 Published Online First 15 April 2024 © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. To cite: Zhang F, Sahu V, Peng K, et al. Gut 2024;73:1280–1291 . ABSTRACT 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 geneTrp53. 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. INTRODUCTION Gastric cancer (GC) is the fourth leading cause of cancer death worldwide, responsible for over 700 000 deaths every year.1 The survival rates of | WHAT IS ALREADY KNOWN ON THIS TOPIC | | --- | | ⇒ Recurrent translocations leading CLDN18-ARHGAP26 fusion proteins have been specifically found in diffuse gastric cancer (DGC) . However, it has been unclear what are the functional effects of CLDN18-ARHGAP26 fusion in the stomach epithelium and potential therapies.
WHAT THIS STUDY ADDS | | ⇒ We functionally demonstrated that the CLDN18-ARHGAP26 fusion acts as an oncogene to promote the function of DGC when combined with Trp53 loss. We also found that focal adhesion kinase (FAK) andYAP were conserved downstream targets

FAQs

What genomic alteration is central to this study of diffuse gastric cancer?

The study focuses on recurrent interchromosomal translations that generate the CLDN18–ARHGAP26 fusion protein in diffuse gastric cancer.

How did the researchers model the CLDN18–ARHGAP26 fusion in vivo and ex vivo?

They used a transgenic mouse model with LSL-CLDN18–ARHGAP26 engineered into the Col1A1 locus, and then studied organoids derived from the model after induction of fusion expression.

What downstream signalling pathways are activated by the CLDN18–ARHGAP26 fusion?

Fusion expression promotes activation of RHOA and downstream effector signalling, including focal adhesion kinase (FAK) activation and induction of the YAP pathway.

Sep 21, 2026

Upload by Liam