2. Academic Validation
  3. A decision point between transdifferentiation and programmed cell death priming controls KRAS-dependent pancreatic cancer development

A decision point between transdifferentiation and programmed cell death priming controls KRAS-dependent pancreatic cancer development

  • Nat Commun. 2025 Feb 19;16(1):1765. doi: 10.1038/s41467-025-56493-7.
Anne T Schneider 1,  Christiane Koppe 1,  Emilie Crouchet 2,  Aristeidis Papargyriou 3 4 5,  Michael T Singer 1,  Veronika Büttner 1,  Leonie Keysberg 1,  Marta Szydlowska 6,  Frank Jühling 2,  Julien Moehlin 2,  Min-Chun Chen 4,  Valentina Leone 3 6 7,  Sebastian Mueller 8 9,  Thorsten Neuß 10,  Mirco Castoldi 1,  Marina Lesina 11,  Frank Bergmann 12 13,  Thilo Hackert 14 15,  Katja Steiger 16,  Wolfram T Knoefel 17,  Alex Zaufel 1,  Jakob N Kather 18 19 20,  Irene Esposito 21,  Matthias M Gaida 22 23 24 25,  Ahmed Ghallab 26 27,  Jan G Hengstler 26,  Henrik Einwächter 4,  Kristian Unger 28 29,  Hana Algül 11,  Nikolaus Gassler 30,  Roland M Schmid 4,  Roland Rad 9 31,  Thomas F Baumert 2 32 33 34,  Maximilian Reichert 3 4 35 36 37,  Mathias Heikenwalder 6 38,  Vangelis Kondylis # 1,  Mihael Vucur # 1,  Tom Luedde # 39 40
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany.
  • 2 University of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease (ITM), UMR_S1110, Strasbourg, France.
  • 3 Translational Pancreatic Cancer Research Center, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
  • 4 Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
  • 5 Institute of Stem Cell Research, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
  • 6 Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 7 Research Unit Radiation Cytogenetics, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  • 8 Institute of Molecular Oncology and Functional Genomics, School of Medicine, TU Munich, Munich, Germany.
  • 9 Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany.
  • 10 Lehrstuhl für Biophysik E27, Center for Protein Assemblies (CPA), Technical University Munich (TUM), Garching, Germany.
  • 11 Comprehensive Cancer Center München, Institute for Tumor Metabolism, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany.
  • 12 Institut of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • 13 Clinical Pathology, Klinikum Darmstadt GmbH, Darmstadt, Germany.
  • 14 Department of General, Visceral, and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany.
  • 15 Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
  • 16 Institute of Pathology, School of Medicine, Technical University of Munich, Munich, Germany.
  • 17 Department of Surgery A, Heinrich-Heine-University Düsseldorf and University Hospital Düsseldorf, Duesseldorf, Germany.
  • 18 Else Kroener Fresenius Center for Digital Health (EFFZ), Technical University Dresden, Dresden, Germany.
  • 19 Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
  • 20 Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany.
  • 21 Institute of Pathology, University Hospital Duesseldorf, Heinrich-Heine University, Duesseldorf, Germany.
  • 22 Institute of Pathology, University Medical Center Mainz, JGU-Mainz, Mainz, Germany.
  • 23 Research Center for Immunotherapy, University Medical Center Mainz, JGU-Mainz, Mainz, Germany.
  • 24 Joint Unit Immunopathology, Institute of Pathology, University Medical Center, JGU-Mainz, Mainz, Germany.
  • 25 TRON, Translational Oncology at the University Medical Center, JGU-Mainz, Mainz, Germany.
  • 26 Leibniz Research Centre for Working Environment and Human Factors (IfADo) at the Technical University Dortmund, Dortmund, Germany.
  • 27 Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.
  • 28 Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany.
  • 29 Research Unit Translational Metabolic Oncology, Institute for Diabetes and Cancer, Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany.
  • 30 Section Pathology of the Institute of Forensic Medicine, University Hospital Jena, Jena, Germany.
  • 31 Department of Internal Medicine II, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
  • 32 Pôle des Pathologies Hépatiques et Digestives, Service d'Hepato-Gastroenterologie, Strasbourg University Hospitals, Strasbourg, France.
  • 33 Institut Hospitalo-Universitaire (IHU) Strasbourg, Strasbourg, France.
  • 34 Institut Universitaire de France (IUF), Paris, France.
  • 35 Center for Organoid Systems (COS), Technical University of Munich, Garching, Germany.
  • 36 Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich, Garching, Germany.
  • 37 German Center for Translational Cancer Research (DKTK), Munich, Germany.
  • 38 The M3 Research Institute, Karls Eberhards Universität Tübingen, Tübingen, Germany.
  • 39 Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany. luedde@hhu.de.
  • 40 Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany. luedde@hhu.de.
  • # Contributed equally.
PMID: 39971907 DOI: 10.1038/s41467-025-56493-7
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-134813
    99.97%, KRAS G12D Inhibitor
    Ras