Journal
ONCOGENE
Volume 41, Issue 43, Pages 4779-4794Publisher
SPRINGERNATURE
DOI: 10.1038/s41388-022-02469-6
Keywords
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Funding
- National Institute of Biomedical Innovation [ID10-41]
- National Cancer Center Research and Development Fund [28-A-11, 29-A-2, 2020-J-2]
- AMED (Japan Agency for Medical Research and Development) [JP20ck0106519]
- Astellas Pharma, Inc [CH27066]
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Frequent gene fusions of ARHGAP6/ARHGAP26 are found in peritoneally-metastasized gastric and pancreatic cancer, leading to downregulation of RhoA-ROCK-MLC2 signaling and cell death. The findings suggest the tumor-suppressive nature of ARHGAP-RhoA signaling and may provide a new avenue for drug discovery against this refractory cancer.
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.
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