Gasdermin C promotes Stemness and Immune Evasion in Pancreatic Cancer via Pyroptosis-Independent Mechanism

Renfei Wu^{1 2}, Jingwei Li^{1 2 3 4}, Alexandra Aicher^{5 6}, Ke Jiang^{1 2}, Serena Tondi⁷, Shuang Dong^{1 2}, Quan Zheng^{1 2}, Siqi Tang⁸, Minchun Chen^{1 2}, Zhenyang Guo^{1 2}, Berina Šabanović⁷, Preeta Ananthanarayanan⁷, Lingxi Jiang^{2 3 4}, Anna Sapino⁹, Chenlei Wen^{2 3 4}, Da Fu^{2 3 4}, Baiyong Shen^{2 3 4}, Christopher Heeschen^{1 2 7}

Affiliations

¹ Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, 227 South Chongqing Road, Shanghai, 200025, P. R. China.
² State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, 227 South Chongqing Road, Shanghai, 200025, P. R. China.
³ Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 227 South Chongqing Road, Shanghai, 200025, P. R. China.
⁴ Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiaotong University School of Medicine, 227 South Chongqing Road, Shanghai, 200025, P. R. China.
⁵ Precision Immunotherapy, Graduate Institute of Biomedical Sciences, China Medical University, No. 91, Xueshi Road, Taichung, 404, Taiwan.
⁶ Immunology Research and Development Center, China Medical University, No. 91, Xueshi Road, Taichung, 404, Taiwan.
⁷ Pancreatic Cancer Heterogeneity, Candiolo Cancer Institute – FPO – IRCCS, Strada Provinciale 142 Km 3,95, Candiolo (TO), 10060, Italy.
⁸ School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, P. R. China.
⁹ Department of Pathology, Candiolo Cancer Institute – FPO – IRCCS, Strada Provinciale 142 Km 3,95, Candiolo (TO), 10060, Italy.

PMID: 39297408
DOI: 10.1002/advs.202308990

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 KRAS^G12D 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.

Keywords: KRAS inhibition; cancer stem cells; gasdermin C; immune evasion; immunotherapy; invasion; metastasis; pancreatic ductal adenocarcinoma.

Adv Sci (Weinh). 2024 Sep 19:e2308990.doi: 10.1002/advs.202308990. Online ahead of print. (IF:15.100).

Gasdermin C promotes Stemness and Immune Evasion in Pancreatic Cancer via Pyroptosis-Independent Mechanism

Abstract

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