Nuclear gasdermin E drives metastatic progression and poor survival in high-grade serous ovarian carcinoma through an ET-1/ZEB1 pathway that can be targeted by ET-1 receptor antagonists.
GSDME acts as a key transcriptional regulator of aggressive behaviors in HG-SOC, which can be targeted by ET-1R antagonists to reduce metastatic burden.
Absolute Event Rate: 0% vs 0%
Abstract Elucidation of the molecular mechanism underlying metastatic dissemination in patients with high-grade serous ovarian carcinoma (HG-SOC) has the potential to affect patient outcome. This study explores the role of gasdermins (GSDMs) in HG-SOC, focusing on novel pyroptosis-independent nuclear functions of GSDME, which are integrated with the endothelin-1 (ET-1)/ET-1 receptor A (ET A R) signaling to sustain metastatic progression. In this tumor, GSDME upregulation is correlated to epithelial-mesenchymal transition (EMT) and ET A R expression. ET-1 signaling fuels GSDME expression by inducing its transcription via the core EMT factors, ZEB1 and ZEB2. GSDME, in turn, translocates to the nucleus to engage ZEB1 and transcriptionally regulate genes coupled with EMT and inflammatory signals, such as E-cadherin, vimentin and interleukin (IL)-6. GSDME depletion, similarly to ZEB1 and ET A R blockade, restrains ET-1-induced EMT phenotypic plasticity and inflammatory cytokine release. Clinically relevant, ET-1 receptor (ET-1R) antagonist, by depleting the nuclear reservoir of the GSDME/ZEB1 transcriptional complex, hinders the metastatic traits of HG-SOC. The intertwined ET A R/GSDME/ZEB1 circuitry characterizes mesenchymal HG-SOC patients and associates with a high-risk of poor survival. Together, these findings unveil GSDME as a key transcriptional regulator of aggressive behaviors and worse prognosis in HG-SOC patients, in an ET-1-driven alliance with ZEB1, which could be targeted by ET-1R antagonist to reduce the metastatic burden of this tumor.
Román et al. (Fri,) reported a other. Nuclear gasdermin E drives metastatic progression and poor survival in high-grade serous ovarian carcinoma through an ET-1/ZEB1 pathway that can be targeted by ET-1 receptor antagonists.