Recurrent RhoGAP gene fusion CLDN18-ARHGAP26 promotes RHOA activation and focal adhesion kinase and YAP-TEAD signalling in diffuse gastric cancer. Gut 2024 Jul 11;73(8):1280-1291
Date
04/16/2024Pubmed ID
38621923Pubmed Central ID
PMC11287566DOI
10.1136/gutjnl-2023-329686Scopus ID
2-s2.0-85191367560 (requires institutional sign-in at Scopus site) 6 CitationsAbstract
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.
Author List
Zhang F, Sahu V, Peng K, Wang Y, Li T, Bala P, Aitymbayev D, Sahgal P, Schaefer A, Der CJ, Ryeom S, Yoon S, Sethi N, Bass AJ, Zhang HAuthor
Antje Schaefer PhD Assistant Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingAnimals
Claudins
DNA-Binding Proteins
Disease Models, Animal
Focal Adhesion Protein-Tyrosine Kinases
GTPase-Activating Proteins
Humans
Mice
Mice, Transgenic
Oncogene Proteins, Fusion
Organoids
Signal Transduction
Stomach Neoplasms
Transcription Factors
rhoA GTP-Binding Protein
