Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic and lethal disease. Gasdermins are primarily associated with necrosis via membrane permeabilization and pyroptosis, a lytic pro-inflammatory type of cell death. In this study, GSDMC upregulation during PDAC progression is reported. GSDMC directly induces genes related to stemness, EMT, and immune evasion. Targeting Gsdmc in murine PDAC models reprograms the immunosuppressive tumor microenvironment, rescuing the recruitment of anti-tumor immune cells through CXCL9. This not only results in diminished tumor initiation, growth and metastasis, but also enhances the response to KRASG12D inhibition and PD-1 checkpoint blockade, respectively. Mechanistically, it is discovered that ADAM17 cleaves GSDMC, releasing nuclear fragments binding to promoter regions of stemness, metastasis, and immune evasion-related genes. Pharmacological inhibition of GSDMC cleavage or prevention of its nuclear translocation is equally effective in suppressing GSDMC's downstream targets and inhibiting PDAC progression. The findings establish GSDMC as a potential therapeutic target for enhancing treatment response in this deadly disease.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Advanced science (Weinheim, Baden-Wurttemberg, Germany)
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
