Gasdermin D Plays an Oncogenic Role in Glioma and Correlates to an Immunosuppressive Microenvironment

Abstract

Background: Understanding the molecular mechanisms driving oncogenic processes in glioma is important in order to develop efficient treatments. Recent studies have proposed gasdermin D (GSDMD) as a newly discovered pyroptosis executive protein associated with tumorigenesis. However, the precise effect of GSDMD on glioma progression remains unknown. Methods: The expression levels of GSDMD in 931 glioma and 1157 normal control tissues were collected. A series of bioinformatic approaches and in vivo and in vitro experiments were used to investigate the roles and mechanisms of GDSMD in glioma. Results: Significant upregulation of GSDMD was detected in glioma tissues compared to normal brain tissues. Patients with glioma and higher GSDMD levels had shorter overall survival, and the Cox regression analysis revealed that GSDMD was an independent risk factor. In addition, upregulation of GSDMD was associated with higher tumor mutation burden and PD-1/PD-L1 expression. Immune infiltration and single-cell analyses indicated that GSDMD was positively associated with an immunosuppressive microenvironment with more infiltrated macrophages and cancer-associated fibroblasts. Furthermore, the in vitro and in vivo experiments revealed that GSDMD knockdown inhibited glioma proliferation, migration, and growth in vivo. Conclusion: Our analyses revealed a relatively comprehensive understanding of the oncogenic role of GSDMD in glioma. GSDMD is a promising prognostic biomarker and a potential target for glioma treatment.

Pyroptosis in glioma: Current management and future application

“…In most cancers, higher levels of focal ptosis are associated with a worse prognosis. 159 Specifically, the expression of PRGs such as CASP3, [160][161][162] CASP4, 163 CASP5, 162,164 CASP6, 165 CASP8, 160,166 GSDMD, 115,162 PLCG1, 162 NLRC4, 167 PRKACA, and ELANE 160 in glioma patients has been found to be negatively correlated with overall survival.…”

“…The treatment of glioma is a highly intriguing subject in the field of neurooncology due to the distinctive structure of the central nervous system, which hinders the penetration of most antitumor drugs into the brain. 115,116 Consequently, the development of effective anti-glioma drugs encounters significant challenges. Despite the numerous advancements in cancer therapies in recent decades, only a limited number have received approval from the US FDA for addressing glioma treatment.…”

Crosstalk between cancer-associated fibroblasts and regulated cell death in tumors: insights into apoptosis, autophagy, ferroptosis, and pyroptosis

“…Nevertheless, there is still limited research on the specific processes and mechanisms by which CAFs directly regulate pyroptosis in tumor cells. Limited data from public databases indicate a positive correlation between CAF infiltration and the expression of GSDMD and GSDME in cancer cells [ 131 , 132 ], suggesting the potential for CAF-induced pyroptosis in cancer cells. In addition, Hou et al identified a non-immune checkpoint function of PD-L1 and demonstrated that PD-L1, cooperated with p-Stat3, could transcriptionally upregulate the expression of GSDMC, leading to the transition of cancer cells from apoptosis to pyroptosis [ 75 ].…”