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 and Tom Luedde ()
Additional contact information
Anne T. Schneider: Medical Faculty at Heinrich-Heine-University
Christiane Koppe: Medical Faculty at Heinrich-Heine-University
Emilie Crouchet: UMR_S1110
Aristeidis Papargyriou: Technical University of Munich
Michael T. Singer: Medical Faculty at Heinrich-Heine-University
Veronika Büttner: Medical Faculty at Heinrich-Heine-University
Leonie Keysberg: Medical Faculty at Heinrich-Heine-University
Marta Szydlowska: German Cancer Research Center (DKFZ)
Frank Jühling: UMR_S1110
Julien Moehlin: UMR_S1110
Min-Chun Chen: Technical University of Munich
Valentina Leone: Technical University of Munich
Sebastian Mueller: TU Munich
Thorsten Neuß: Technical University Munich (TUM)
Mirco Castoldi: Medical Faculty at Heinrich-Heine-University
Marina Lesina: Technical University of Munich
Frank Bergmann: Heidelberg University Hospital
Thilo Hackert: University Hospital Heidelberg
Katja Steiger: Technical University of Munich
Wolfram T. Knoefel: Heinrich-Heine-University Düsseldorf and University Hospital Düsseldorf
Alex Zaufel: Medical Faculty at Heinrich-Heine-University
Jakob N. Kather: Technical University Dresden
Irene Esposito: Heinrich-Heine University
Matthias M. Gaida: 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: Technical University of Munich
Kristian Unger: LMU Munich
Hana Algül: Technical University of Munich
Nikolaus Gassler: University Hospital Jena
Roland M. Schmid: Technical University of Munich
Roland Rad: Technical University of Munich
Thomas F. Baumert: UMR_S1110
Maximilian Reichert: Technical University of Munich
Mathias Heikenwalder: German Cancer Research Center (DKFZ)
Vangelis Kondylis: Medical Faculty at Heinrich-Heine-University
Mihael Vucur: Medical Faculty at Heinrich-Heine-University
Tom Luedde: Medical Faculty at Heinrich-Heine-University

Nature Communications, 2025, vol. 16, issue 1, 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.

Date: 2025
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DOI: 10.1038/s41467-025-56493-7

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