ARHGAP-RhoA signaling provokes homotypic adhesion-triggered cell death of metastasized diffuse-type gastric cancer.

Autor: Komatsu M; Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan. makomats@ncc.go.jp., Ichikawa H; Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan., Chiwaki F; Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan., Sakamoto H; Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan., Komatsuzaki R; Division of Cancer Therapeutics, National Cancer Center Research Institute, Tokyo, Japan., Asaumi M; Advanced Informatics and Analytics, Astellas Pharma Inc, Ibaraki, Japan., Tsunoyama K; Advanced Informatics and Analytics, Astellas Pharma Inc, Ibaraki, Japan., Fukagawa T; Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan., Matsushita H; Department of Laboratory Medicine, National Cancer Center Hospital, Tokyo, Japan., Boku N; Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan., Matsusaki K; Ascites Treatment Center, Kanamecho Hospital, Tokyo, Japan., Takeshita F; Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan., Yoshida T; Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan., Sasaki H; Department of Translational Oncology, National Cancer Center Research Institute, Tokyo, Japan. hksasaki@ncc.go.jp.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2022 Oct; Vol. 41 (43), pp. 4779-4794. Date of Electronic Publication: 2022 Sep 20.
DOI: 10.1038/s41388-022-02469-6
Abstrakt: Genetic alteration of Rho GTPase-activating proteins (ARHGAP) and GTPase RhoA is a hallmark of diffuse-type gastric cancer and elucidating its biological significance is critical to comprehensively understanding this malignancy. Here, we report that gene fusions of ARHGAP6/ARHGAP26 are frequent genetic events in peritoneally-metastasized gastric and pancreatic cancer. From the malignant ascites of patients, we established gastric cancer cell lines that spontaneously gain hotspot RHOA mutations or four different ARHGAP6/ARHGAP26 fusions. These alterations critically downregulate RhoA-ROCK-MLC2 signaling, which elicits cell death. Omics and functional analyses revealed that the downstream signaling initiates actin stress fibers and reinforces intercellular junctions via several types of catenin. E-cadherin-centered homotypic adhesion followed by lysosomal membrane permeabilization is a pivotal mechanism in cell death. These findings support the tumor-suppressive nature of ARHGAP-RhoA signaling and might indicate a new avenue of drug discovery against this refractory cancer.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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