Gasdermin C promotes Stemness and Immune Evasion in Pancreatic Cancer via Pyroptosis‐Independent Mechanism
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 KRAS<sup>G12D</sup> 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.
Authors
- Da Fu (ORCID: https://orcid.org/0000-0002-0878-2575)
- Alexandra Aicher (ORCID: https://orcid.org/0000-0002-8920-9577)
- Lingxi Jiang (ORCID: https://orcid.org/0000-0001-6037-6972)
- Berina Šabanović (ORCID: https://orcid.org/0000-0002-0883-3248)
- Siqi Tang (ORCID: https://orcid.org/0000-0001-6023-7294)
- Zhenyang Guo
- Serena Tondi (ORCID: https://orcid.org/0009-0003-6677-9766)
- Christopher Heeschen (ORCID: https://orcid.org/0000-0002-1158-8554)
- Preeta Ananthanarayanan (ORCID: https://orcid.org/0000-0002-9900-0435)
- Minchun Chen (ORCID: https://orcid.org/0000-0002-7380-1365)
- Ke Jiang (ORCID: https://orcid.org/0000-0001-7959-7716)
- Chenlei Wen (ORCID: https://orcid.org/0000-0003-3458-5409)
- Anna Sapino (ORCID: https://orcid.org/0000-0003-3542-9571)
- Jingwei Li (ORCID: https://orcid.org/0000-0002-5341-2776)
- Quan Zheng (ORCID: https://orcid.org/0000-0002-4512-9233)
- Renfei Wu (ORCID: https://orcid.org/0000-0002-1817-0388)
- Baiyong Shen
- Shuang Lin Dong
Institutions
- East China University of Science and Technology (CN)
- Shanghai Jiao Tong University (CN)
- China Medical University (TW)
- Ruijin Hospital (CN)
- Shanghai Cancer Institute (CN)
- Candiolo Cancer Institute (IT)
Publication Details
- Journal
- Advanced Science
- Published
- 2024-09-19
- DOI
- https://doi.org/10.1002/advs.202308990
- Citations
- 13
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 3.04
Funders
- Shanghai Municipal Education Commission
- Ministry of Science and Technology, Taiwan