Gasdermin E-mediated lysosome-pore formation curbs pancreatic ductal adenocarcinoma via IFN-γ/IFN-β/TGF-β cocktail mRNA-LNP

Grossberg AJ, Chu LC, Deig CR, Fishman EK, Hwang WL, Maitra A, et al. Multidisciplinary standards of care and recent progress in pancreatic ductal adenocarcinoma. CA Cancer J Clin. 2020;70:375–403. https://doi.org/10.3322/caac.21626.

Article  PubMed  PubMed Central  Google Scholar 

Bear AS, Vonderheide RH, O’Hara MH. Challenges and Opportunities for Pancreatic Cancer Immunotherapy. Cancer Cell. 2020;38:788–802. https://doi.org/10.1016/j.ccell.2020.08.004.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Christenson ES, Jaffee E, Azad NS. Current and emerging therapies for patients with advanced pancreatic ductal adenocarcinoma: a bright future. Lancet Oncol. 2020;21:e135–e45. https://doi.org/10.1016/s1470-2045(19)30795-8.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Khorana AA, Ahrendt SA, Ryan CK, Francis CW, Hruban RH, Hu YC, et al. Tissue factor expression, angiogenesis, and thrombosis in pancreatic cancer. Clin Cancer Res. 2007;13:2870–5. https://doi.org/10.1158/1078-0432.Ccr-06-2351.

Article  CAS  PubMed  Google Scholar 

Khorana AA, Fine RL. Pancreatic cancer and thromboembolic disease. Lancet Oncol. 2004;5:655–63. https://doi.org/10.1016/s1470-2045(04)01606-7.

Article  CAS  PubMed  Google Scholar 

Risman RA, Milman N, Sinan H, Tutwiler V. Clot formation, structure, and fibrinolysis of pancreatic cancer patients. Res Sq. 2025. https://doi.org/10.21203/rs.3.rs-5868575/v1.

Wahab R, Hasan MM, Azam Z, Grippo PJ, Al-Hilal TA. The role of coagulome in the tumor immune microenvironment. Adv Drug Deliv Rev. 2023;200:115027. https://doi.org/10.1016/j.addr.2023.115027.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Frere C, Bournet B, Gourgou S, Fraisse J, Canivet C, Connors JM, et al. Incidence of Venous Thromboembolism in Patients With Newly Diagnosed Pancreatic Cancer and Factors Associated With Outcomes. Gastroenterology. 2020;158:1346–58.e4. https://doi.org/10.1053/j.gastro.2019.12.009.

Article  PubMed  Google Scholar 

Lv J, Zhou Y, Zhou N, Wang Z, Chen J, Chen H, et al. Epigenetic modification of CSDE1 locus dictates immune recognition of nascent tumorigenic cells. Sci Transl Med. 2023;15:eabq6024. https://doi.org/10.1126/scitranslmed.abq6024.

Article  CAS  PubMed  Google Scholar 

Lv J, Liu X, Zhou Y, Cheng F, Chen H, Li S, et al. YAP Inactivation by Soft Mechanotransduction Relieves MAFG for Tumor Cell Dedifferentiation. Res (Wash D C). 2023;6:0215. https://doi.org/10.34133/research.0215.

Article  CAS  Google Scholar 

Liu Y, Liang X, Dong W, Fang Y, Lv J, Zhang T, et al. Tumor-Repopulating Cells Induce PD-1 Expression in CD8(+) T Cells by Transferring Kynurenine and AhR Activation. Cancer Cell. 2018;33:480–94.e7. https://doi.org/10.1016/j.ccell.2018.02.005.

Article  CAS  PubMed  Google Scholar 

Liu J, Tan Y, Zhang H, Zhang Y, Xu P, Chen J, et al. Soft fibrin gels promote selection and growth of tumorigenic cells. Nat Mater. 2012;11:734–41. https://doi.org/10.1038/nmat3361.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Liu Y, Zhang T, Zhang H, Li J, Zhou N, Fiskesund R, et al. Cell Softness Prevents Cytolytic T-cell Killing of Tumor-Repopulating Cells. Cancer Res. 2021;81:476–88. https://doi.org/10.1158/0008-5472.Can-20-2569.

Article  CAS  PubMed  Google Scholar 

Ma J, Zhang Y, Tang K, Zhang H, Yin X, Li Y, et al. Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles. Cell Res. 2016;26:713–27. https://doi.org/10.1038/cr.2016.53.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lv J, Liu Y, Mo S, Zhou Y, Chen F, Cheng F, et al. Gasdermin E mediates resistance of pancreatic adenocarcinoma to enzymatic digestion through a YBX1-mucin pathway. Nat Cell Biol. 2022;24:364–72. https://doi.org/10.1038/s41556-022-00857-4.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Borden EC. Interferons α and β in cancer: therapeutic opportunities from new insights. Nat Rev Drug Discov. 2019;18:219–34. https://doi.org/10.1038/s41573-018-0011-2.

Article  CAS  PubMed  Google Scholar 

Ivashkiv LB. IFNγ: signaling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat Rev Immunol. 2018;18:545–58. https://doi.org/10.1038/s41577-018-0029-z.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Liu Y, Liang X, Yin X, Lv J, Tang K, Ma J, et al. Blockade of IDO-kynurenine-AhR metabolic circuitry abrogates IFN-γ-induced immunologic dormancy of tumor-repopulating cells. Nat Commun. 2017;8:15207. https://doi.org/10.1038/ncomms15207.

Article  PubMed  PubMed Central  Google Scholar 

Liu Y, Lv J, Liu J, Liang X, Jin X, Xie J, et al. STAT3/p53 pathway activation disrupts IFN-β-induced dormancy in tumor-repopulating cells. J Clin Invest. 2018;128:1057–73. https://doi.org/10.1172/jci96329.

Article  PubMed  PubMed Central  Google Scholar 

Prunier C, Baker D, Ten Dijke P, Ritsma L. TGF-β Family Signaling Pathways in Cellular Dormancy. Trends Cancer. 2019;5:66–78. https://doi.org/10.1016/j.trecan.2018.10.010.

Article  CAS  PubMed  Google Scholar 

Carneiro BA, El-Deiry WS. Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol. 2020;17:395–417. https://doi.org/10.1038/s41571-020-0341-y.

Article  PubMed  PubMed Central  Google Scholar 

Chen KW, Broz P. Gasdermins as evolutionarily conserved executors of inflammation and cell death. Nat Cell Biol. 2024;26:1394–406. https://doi.org/10.1038/s41556-024-01474-z.

Article  CAS  PubMed  Google Scholar 

Broz P, Pelegrín P, Shao F. The gasdermins, a protein family executing cell death and inflammation. Nat Rev Immunol. 2020;20:143–57. https://doi.org/10.1038/s41577-019-0228-2.

Article  CAS  PubMed  Google Scholar 

Miao R, Jiang C, Chang WY, Zhang H, An J, Ho F, et al. Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis. Immunity. 2023;56:2523–41.e8. https://doi.org/10.1016/j.immuni.2023.10.004.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Liu Y, Zhang T, Zhou Y, Li J, Liang X, Zhou N, et al. Visualization of perforin/gasdermin/complement-formed pores in real cell membranes using atomic force microscopy. Cell Mol Immunol. 2019;16:611–20. https://doi.org/10.1038/s41423-018-0165-1.

Article  CAS  PubMed  Google Scholar 

Wang Y, Gao W, Shi X, Ding J, Liu W, He H, et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 2017;547:99–103. https://doi.org/10.1038/nature22393.

Article  CAS  PubMed  Google Scholar 

Ruiz-Blázquez P, Pistorio V, Fernández-Fernández M, Moles A. The multifaceted role of cathepsins in liver disease. J Hepatol. 2021;75:1192–202. https://doi.org/10.1016/j.jhep.2021.06.031.

Article  CAS  PubMed  Google Scholar 

Zhang H, Liu J, Yuan W, Zhang Q, Luo X, Li Y, et al. Ammonia-induced lysosomal and mitochondrial damage causes cell death of effector CD8(+) T cells. Nat Cell Biol. 2024;26:1892–902. https://doi.org/10.1038/s41556-024-01503-x.

Article  CAS  PubMed 

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