ArticleNature communications2025
A decision point between transdifferentiation and programmed cell death priming controls KRAS-dependent pancreatic cancer development.
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Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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9citing papers in PubMed
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Who cites it
9 citing papers in PubMed.
- Oncogenic KRAS-driven type I interferon signalling primes pancreatic cancer for necroptosis.Nature communications · 2026Article
- Klf4-Tymp axis promotes inflammation-driven early tumorigenesis by enhancing kras mutation-induced acinar-to-ductal metaplasia through Pi3k/Akt and Mek/Erk pathways.Journal of experimental & clinical cancer research : CR · 2026Article
- From Cell-Free Transcriptomes to Single-Cell Landscapes: Biomarker Discovery and Originating Cell Alteration Analysis via Graph Matrix Factorization.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Regulated necrosis at the crossroads of liver inflammation and cancer development.Nature reviews. Gastroenterology & hepatology · 2026Review
- Adipogenic transdifferentiation reprograms EMT-high PDAC cells into a post-mitotic adipocyte-like state and limits metastasis.Cell death & disease · 2026Article
- Targeting TRIM25 as a therapeutic strategy to enhance ferroptosis in glioblastoma cells.Journal of nanobiotechnology · 2026Article
- NG25 Enhances Anti-Tumor Immunity inOncoTargets and therapy · 2026Article
- Prognostic significance of advanced lung cancer inflammation index in resectable pancreatic cancer: A retrospective study.World journal of gastrointestinal surgery · 2025Article
- The role of circRNAs in NScience progressReview
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Authors and funding
38 authors.
Anne T SchneiderDepartment of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany.
Christiane KoppeDepartment of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany.
Emilie CrouchetUniversity of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease (ITM), UMR_S1110, Strasbourg, France.
Aristeidis PapargyriouTranslational Pancreatic Cancer Research Center, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.ORCID http://orcid.org/0000-0002-2577-4737
Michael T SingerDepartment of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany.
Veronika BüttnerDepartment of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany.
Leonie KeysbergDepartment of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany.
Marta SzydlowskaDivision of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.ORCID http://orcid.org/0000-0002-4660-899X
Frank JühlingUniversity of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease (ITM), UMR_S1110, Strasbourg, France.
Julien MoehlinUniversity of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease (ITM), UMR_S1110, Strasbourg, France.
Min-Chun ChenKlinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.ORCID http://orcid.org/0000-0002-9478-9836
Valentina LeoneTranslational Pancreatic Cancer Research Center, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Sebastian MuellerInstitute of Molecular Oncology and Functional Genomics, School of Medicine, TU Munich, Munich, Germany.ORCID http://orcid.org/0009-0008-1514-3027
Thorsten NeußLehrstuhl für Biophysik E27, Center for Protein Assemblies (CPA), Technical University Munich (TUM), Garching, Germany.ORCID http://orcid.org/0009-0002-2230-9028
Mirco CastoldiDepartment of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany.ORCID http://orcid.org/0000-0003-2484-936X
Marina LesinaComprehensive Cancer Center München, Institute for Tumor Metabolism, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany.
Frank BergmannInstitut of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Thilo HackertDepartment of General, Visceral, and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany.ORCID http://orcid.org/0000-0002-7012-1196
Katja SteigerInstitute of Pathology, School of Medicine, Technical University of Munich, Munich, Germany.ORCID http://orcid.org/0000-0002-7269-5433
Wolfram T KnoefelDepartment of Surgery A, Heinrich-Heine-University Düsseldorf and University Hospital Düsseldorf, Duesseldorf, Germany.
Alex ZaufelDepartment of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany.
Jakob N KatherElse Kroener Fresenius Center for Digital Health (EFFZ), Technical University Dresden, Dresden, Germany.ORCID http://orcid.org/0000-0002-3730-5348
Irene EspositoInstitute of Pathology, University Hospital Duesseldorf, Heinrich-Heine University, Duesseldorf, Germany.
Matthias M GaidaInstitute of Pathology, University Medical Center Mainz, JGU-Mainz, Mainz, Germany.
Ahmed GhallabLeibniz Research Centre for Working Environment and Human Factors (IfADo) at the Technical University Dortmund, Dortmund, Germany.ORCID http://orcid.org/0000-0003-0695-3403
Jan G HengstlerLeibniz Research Centre for Working Environment and Human Factors (IfADo) at the Technical University Dortmund, Dortmund, Germany.ORCID http://orcid.org/0000-0002-1427-5246
Henrik EinwächterKlinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Kristian UngerDepartment of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany.
Hana AlgülComprehensive Cancer Center München, Institute for Tumor Metabolism, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany.ORCID http://orcid.org/0000-0002-5067-7031
Nikolaus GasslerSection Pathology of the Institute of Forensic Medicine, University Hospital Jena, Jena, Germany.
Roland M SchmidKlinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Roland RadCenter for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.ORCID http://orcid.org/0000-0002-6849-9659
Thomas F BaumertUniversity of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease (ITM), UMR_S1110, Strasbourg, France.ORCID http://orcid.org/0000-0002-8864-2168
Maximilian ReichertTranslational Pancreatic Cancer Research Center, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Mathias HeikenwalderDivision of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.ORCID http://orcid.org/0000-0002-3135-2274
Vangelis Kondylis *Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany.ORCID http://orcid.org/0000-0002-6970-8731
Mihael Vucur *Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany.ORCID http://orcid.org/0000-0003-4078-1668
Tom Luedde *Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany. luedde@hhu.de.ORCID http://orcid.org/0000-0002-6288-8821
Funding
Agence Nationale de la Recherche (French National Research Agency) ANR-10-LABX-0028_HEPSYSBundesministerium für Bildung und Forschung (Federal Ministry of Education and Research) 01KD2206PBundesministerium für Bildung und Forschung (Federal Ministry of Education and Research) 01KD2208BBundesministerium für Bildung und Forschung (Federal Ministry of Education and Research) 13N16450Deutsche Forschungsgemeinschaft (German Research Foundation) 279874820Deutsche Forschungsgemeinschaft (German Research Foundation) 440603844Deutsche Forschungsgemeinschaft (German Research Foundation) 457724578Deutsche Forschungsgemeinschaft (German Research Foundation) 493659010Deutsche Forschungsgemeinschaft (German Research Foundation) SFB1321Deutsche Forschungsgemeinschaft (German Research Foundation) SFB-TR179Deutsche Forschungsgemeinschaft (German Research Foundation) SFB-TR209Deutsche Krebshilfe (German Cancer Aid) 111273Deutsche Krebshilfe (German Cancer Aid) 70114893Deutsche Krebshilfe (German Cancer Aid) SFB-CRC 1382EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council) 771083EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020) 667273European Research Council 101021417
Abstract
KRAS-dependent acinar-to-ductal metaplasia (ADM) is a fundamental step in the development of pancreatic ductal adenocarcinoma (PDAC), but the involvement of cell death pathways remains unclear. Here, we show that key regulators of programmed cell death (PCD) become upregulated during KRAS-driven ADM, thereby priming transdifferentiated cells to death. Using transgenic mice and primary cell and organoid cultures, we show that transforming growth factor (TGF)-β-activated kinase 1 (TAK1), a kinase regulating cell survival and inflammatory pathways, prevents the elimination of transdifferentiated cells through receptor-interacting protein kinase 1 (RIPK1)-mediated apoptosis and necroptosis, enabling PDAC development. Accordingly, pharmacological inhibition of TAK1 induces PCD in patient-derived PDAC organoids. Importantly, cell death induction via TAK1 inhibition does not appear to elicit an overt injury-associated inflammatory response. Collectively, these findings suggest that TAK1 supports cellular plasticity by suppressing spontaneous PCD activation during ADM, representing a promising pharmacological target for the prevention and treatment of PDAC.
Indexed as
ApoptosisCarcinoma, Pancreatic DuctalCell TransdifferentiationPancreatic NeoplasmsProto-Oncogene Proteins p21(ras)AnimalsCell Line, TumorHumansMAP Kinase Kinase Kinase 7MAP Kinase Kinase KinasesMiceMice, TransgenicNecroptosisOrganoidsHras protein, mouseKRAS protein, humanMAP Kinase Kinase Kinase 7MAP Kinase Kinase KinasesProto-Oncogene Proteins p21(ras)
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