Nuclear gasdermin E drives endothelin-1-induced metastatic progression independently of the pyroptosis

TL;DR

This study reveals that gasdermin E (GSDME) promotes metastasis in ovarian cancer by working with other proteins, offering a new target for treatment.

Contribution

The paper identifies a novel nuclear function of GSDME in promoting metastasis, independent of pyroptosis, and links it to the ET-1/ZEB1 signaling pathway.

Findings

GSDME upregulation correlates with epithelial-mesenchymal transition and ETAR expression in high-grade serous ovarian carcinoma.

ET-1 signaling increases GSDME expression via ZEB1 and ZEB2, which in turn regulates genes involved in metastasis and inflammation.

Blocking ET-1 receptor or depleting GSDME reduces metastatic traits and inflammatory cytokine release in the tumor.

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 (ETAR) signaling to sustain metastatic progression. In this tumor, GSDME upregulation is correlated to epithelial-mesenchymal transition (EMT) and ETAR 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 ETAR 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 ETAR/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.

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