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

被引:2
作者
Wu, Renfei [1 ,2 ]
Li, Jingwei [1 ,2 ,3 ,4 ]
Aicher, Alexandra [5 ,6 ]
Jiang, Ke [1 ,2 ]
Tondi, Serena [7 ]
Dong, Shuang [1 ,2 ]
Zheng, Quan [1 ,2 ]
Tang, Siqi [8 ]
Chen, Minchun [1 ,2 ]
Guo, Zhenyang [1 ,2 ]
Sabanovic, Berina [7 ]
Ananthanarayanan, Preeta [7 ]
Jiang, Lingxi [2 ,3 ,4 ]
Sapino, Anna [9 ]
Wen, Chenlei [2 ,3 ,4 ]
Fu, Da [2 ,3 ,4 ]
Shen, Baiyong [2 ,3 ,4 ]
Heeschen, Christopher [1 ,2 ,7 ]
机构
[1] Shanghai Jiao Tong Univ, Ctr Single Cell Om, Sch Publ Hlth, Sch Med, 227 South Chongqing Rd, Shanghai 200025, Peoples R China
[2] Shanghai Jiao Tong Univ, Sch Med, State Key Lab Syst Med Canc, 227 South Chongqing Rd, Shanghai 200025, Peoples R China
[3] Shanghai Jiao Tong Univ, Ruijin Hosp, Pancreat Dis Ctr, Dept Gen Surg,Sch Med, 227 South Chongqing Rd, Shanghai 200025, Peoples R China
[4] Shanghai Jiao Tong Univ, Res Inst Pancreat Dis, Sch Med, Shanghai Key Lab Translat Res Pancreat Neoplasms, 227 South Chongqing Rd, Shanghai 200025, Peoples R China
[5] China Med Univ, Grad Inst Biomed Sci, Precis Immunotherapy, 91 Xueshi Rd, Taichung 404, Taiwan
[6] China Med Univ, Immunol Res & Dev Ctr, 91 Xueshi Rd, Taichung 404, Taiwan
[7] IRCCS, Candiolo Canc Inst, Pancreat Canc Heterogene, FPO, Str Provinciale 142 Km 3 95, I-10060 Candiolo, TO, Italy
[8] East China Univ Sci & Technol, Sch Pharm, 130 Meilong Rd, Shanghai 200237, Peoples R China
[9] IRCCS, Candiolo Canc Inst, Dept Pathol, FPO, Str Provinciale 142 Km 3 95, I-10060 Candiolo, TO, Italy
关键词
cancer stem cells; gasdermin C; immune evasion; invasion; immunotherapy; KRAS inhibition; metastasis; pancreatic ductal adenocarcinoma; EXPRESSION; TARGET; CELLS; KRAS(G12D); IVERMECTIN; INHIBITOR; CLEAVAGE; EFFICACY; DRUG;
D O I
10.1002/advs.202308990
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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. This study unveils Gasdermin C (GSDMC) as a transcriptional master regulator of stemness and immune evasion in pancreatic ductal adenocarcinoma, acting downstream of EMT-inducing factors. Mechanistically, GSDMC blocks the T cell-recruiting chemokine CXCL9 and directly upregulates stemness and immune checkpoing molecules. Genetic or pharmacological targeting of GSDMC might be useful for enhancing response to immunotherapy in this still deadly disease. image
引用
收藏
页数:24
相关论文
共 50 条
  • [1] Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma
    Alonso-Nocelo, Marta
    Ruiz-Canas, Laura
    Sancho, Patricia
    Gorgulu, Kivanc
    Alcala, Sonia
    Pedrero, Coral
    Vallespinos, Mireia
    Carlos Lopez-Gil, Juan
    Ochando, Marina
    Garcia-Garcia, Elena
    David Trabulo, Sara Maria
    Martinelli, Paola
    Sanchez-Tomero, Patricia
    Sanchez-Palomo, Carmen
    Gonzalez-Santamaria, Patricia
    Yuste, Lourdes
    Wormann, Sonja Maria
    Kabacaoglu, Derya
    Earl, Julie
    Martin, Alberto
    Salvador, Fernando
    Valle, Sandra
    Martin-Hijano, Laura
    Carrato, Alfredo
    Erkan, Mert
    Garcia-Bermejo, Laura
    Hermann, Patrick C.
    Algul, Hana
    Moreno-Bueno, Gema
    Heeschen, Christopher
    Portillo, Francisco
    Cano, Amparo
    Sainz, Bruno, Jr.
    [J]. GUT, 2023, 72 (02) : 345 - 359
  • [2] Global Burden of 5 Major Types of Gastrointestinal Cancer
    Arnold, Melina
    Abnet, Christian C.
    Neale, Rachel E.
    Vignat, Jerome
    Giovannucci, Edward L.
    McGlynn, Katherine A.
    Bray, Freddie
    [J]. GASTROENTEROLOGY, 2020, 159 (01) : 335 - +
  • [3] CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy
    Barkal, Amira A.
    Brewer, Rachel E.
    Markovic, Maxim
    Kowarsky, Mark
    Barkal, Sammy A.
    Zaro, Balyn W.
    Krishnan, Venkatesh
    Hatakeyama, Jason
    Dorigo, Oliver
    Barkal, Layla J.
    Weissman, Irving L.
    [J]. NATURE, 2019, 572 (7769) : 392 - +
  • [4] The COPI system: Molecular mechanisms and function
    Beck, R.
    Ravet, M.
    Wieland, F. T.
    Cassel, D.
    [J]. FEBS LETTERS, 2009, 583 (17) : 2701 - 2709
  • [5] Bray F, 2018, CA-CANCER J CLIN, V68, P1, DOI [DOI 10.3322/CANJCLIN.49.1.33, 10.3322/caac.21492, DOI 10.3322/caac.20115]
  • [6] Callaway E, 2015, NATURE, V526, P174, DOI 10.1038/nature.2015.18507
  • [7] Proteogenomic characterization of pancreatic ductal adenocarcinoma
    Cao, Liwei
    Huang, Chen
    Zhou, Daniel Cui
    Hu, Yingwei
    Lih, T. Mamie
    Savage, Sara R.
    Krug, Karsten
    Clark, David J.
    Schnaubelt, Michael
    Chen, Lijun
    Leprevost, Felipe da Veiga
    Eguez, Rodrigo Vargas
    Yang, Weiming
    Pan, Jianbo
    Wen, Bo
    Dou, Yongchao
    Jiang, Wen
    Liao, Yuxing
    Shi, Zhiao
    Terekhanova, Nadezhda, V
    Cao, Song
    Lu, Rita Jui-Hsien
    Li, Yize
    Liu, Ruiyang
    Zhu, Houxiang
    Ronning, Peter
    Wu, Yige
    Wyczalkowski, Matthew A.
    Easwaran, Hariharan
    Danilova, Ludmila
    Mer, Arvind Singh
    Yoo, Seungyeul
    Wang, Joshua M.
    Liu, Wenke
    Haibe-Kains, Benjamin
    Thiagarajan, Mathangi
    Jewell, Scott D.
    Hostetter, Galen
    Newton, Chelsea J.
    Li, Qing Kay
    Roehr, Michael H.
    Fenyo, David
    Wang, Pei
    Nesvizhskii, Alexey, I
    Mani, D. R.
    Omenn, Gilbert S.
    Boja, Emily S.
    Mesri, Mehdi
    Robles, Ana, I
    Rodriguez, Henry
    [J]. CELL, 2021, 184 (19) : 5031 - +
  • [8] Inhibition of CD47 Effectively Targets Pancreatic Cancer Stem Cells via Dual Mechanisms
    Cioffi, Michele
    Trabulo, Sara
    Hidalgo, Manuel
    Costello, Eithne
    Greenhalf, William
    Erkan, Mert
    Kleeff, Joerg
    Sainz, Bruno, Jr.
    Heeschen, Christopher
    [J]. CLINICAL CANCER RESEARCH, 2015, 21 (10) : 2325 - 2337
  • [9] FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer
    Conroy, Thierry
    Desseigne, Francoise
    Ychou, Marc
    Bouche, Olivier
    Guimbaud, Rosine
    Becouarn, Yves
    Adenis, Antoine
    Raoul, Jean-Luc
    Gourgou-Bourgade, Sophie
    de la Fouchardiere, Christelle
    Bennouna, Jaafar
    Bachet, Jean-Baptiste
    Khemissa-Akouz, Faiza
    Pere-Verge, Denis
    Delbaldo, Catherine
    Assenat, Eric
    Chauffert, Bruno
    Michel, Pierre
    Montoto-Grillot, Christine
    Ducreux, Michel
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2011, 364 (19) : 1817 - 1825
  • [10] High Expression of GSDMC Is Associated with Poor Survival in Kidney Clear Cell Cancer
    Cui, Yun-Qian
    Meng, Fei
    Zhan, Wen-Li
    Dai, Zhou-Tong
    Liao, Xinghua
    [J]. BIOMED RESEARCH INTERNATIONAL, 2021, 2021