Nature Communications (Feb 2025)
A decision point between transdifferentiation and programmed cell death priming controls KRAS-dependent pancreatic cancer development
- Anne T. Schneider,
- Christiane Koppe,
- Emilie Crouchet,
- Aristeidis Papargyriou,
- Michael T. Singer,
- Veronika Büttner,
- Leonie Keysberg,
- Marta Szydlowska,
- Frank Jühling,
- Julien Moehlin,
- Min-Chun Chen,
- Valentina Leone,
- Sebastian Mueller,
- Thorsten Neuß,
- Mirco Castoldi,
- Marina Lesina,
- Frank Bergmann,
- Thilo Hackert,
- Katja Steiger,
- Wolfram T. Knoefel,
- Alex Zaufel,
- Jakob N. Kather,
- Irene Esposito,
- Matthias M. Gaida,
- Ahmed Ghallab,
- Jan G. Hengstler,
- Henrik Einwächter,
- Kristian Unger,
- Hana Algül,
- Nikolaus Gassler,
- Roland M. Schmid,
- Roland Rad,
- Thomas F. Baumert,
- Maximilian Reichert,
- Mathias Heikenwalder,
- Vangelis Kondylis,
- Mihael Vucur,
- Tom Luedde
Affiliations
- Anne T. Schneider
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University
- Christiane Koppe
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University
- Emilie Crouchet
- University of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease (ITM), UMR_S1110
- Aristeidis Papargyriou
- Translational Pancreatic Cancer Research Center, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich
- Michael T. Singer
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University
- Veronika Büttner
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University
- Leonie Keysberg
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University
- Marta Szydlowska
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ)
- Frank Jühling
- University of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease (ITM), UMR_S1110
- Julien Moehlin
- University of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease (ITM), UMR_S1110
- Min-Chun Chen
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich
- Valentina Leone
- Translational Pancreatic Cancer Research Center, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich
- Sebastian Mueller
- Institute of Molecular Oncology and Functional Genomics, School of Medicine, TU Munich
- Thorsten Neuß
- Lehrstuhl für Biophysik E27, Center for Protein Assemblies (CPA), Technical University Munich (TUM)
- Mirco Castoldi
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University
- Marina Lesina
- Comprehensive Cancer Center München, Institute for Tumor Metabolism, TUM School of Medicine and Health, Technical University of Munich
- Frank Bergmann
- Institut of Pathology, Heidelberg University Hospital
- Thilo Hackert
- Department of General, Visceral, and Transplantation Surgery, University Hospital Heidelberg
- Katja Steiger
- Institute of Pathology, School of Medicine, Technical University of Munich
- Wolfram T. Knoefel
- Department of Surgery A, Heinrich-Heine-University Düsseldorf and University Hospital Düsseldorf
- Alex Zaufel
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University
- Jakob N. Kather
- Else Kroener Fresenius Center for Digital Health (EFFZ), Technical University Dresden
- Irene Esposito
- Institute of Pathology, University Hospital Duesseldorf, Heinrich-Heine University
- Matthias M. Gaida
- Institute of Pathology, University Medical Center Mainz, JGU-Mainz
- Ahmed Ghallab
- Leibniz Research Centre for Working Environment and Human Factors (IfADo) at the Technical University Dortmund
- Jan G. Hengstler
- Leibniz Research Centre for Working Environment and Human Factors (IfADo) at the Technical University Dortmund
- Henrik Einwächter
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich
- Kristian Unger
- Department of Radiation Oncology, University Hospital, LMU Munich
- Hana Algül
- Comprehensive Cancer Center München, Institute for Tumor Metabolism, TUM School of Medicine and Health, Technical University of Munich
- Nikolaus Gassler
- Section Pathology of the Institute of Forensic Medicine, University Hospital Jena
- Roland M. Schmid
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich
- Roland Rad
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich
- Thomas F. Baumert
- University of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease (ITM), UMR_S1110
- Maximilian Reichert
- Translational Pancreatic Cancer Research Center, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich
- Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ)
- Vangelis Kondylis
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University
- Mihael Vucur
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University
- Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University
- DOI
- https://doi.org/10.1038/s41467-025-56493-7
- Journal volume & issue
-
Vol. 16,
no. 1
pp. 1 – 18
Abstract
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.
