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Schneider, A.T.* ; Koppe, C.* ; Crouchet, E.* ; Papargyriou, A. ; Singer, M.T.* ; Büttner, V.* ; Keysberg, L.S.* ; Szydlowska, M.* ; Jühling, F.* ; Moehlin, J.* ; Chen, M.C.* ; Leone, V. ; Mueller, S.* ; Neuß, T.* ; Castoldi, M.* ; Lesina, M.* ; Bergmann, F.* ; Hackert, T.* ; Steiger, K.* ; Knoefel, W.T.* ; Zaufel, A.* ; Kather, J.N.* ; Esposito, I.* ; Gaida, M.M.* ; Ghallab, A.* ; Hengstler, J.G.* ; Einwächter, H.* ; Unger, K. ; Algül, H.* ; Gassler, N.* ; Schmid, R.M.* ; Rad, R.* ; Baumert, T.F.* ; Reichert, M.* ; Heikenwalder, M.* ; Kondylis, V.* ; Vucur, M.* ; Luedde, T.*

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

Nat. Commun. 16:1765 (2025)
Publ. Version/Full Text DOI PMC
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Nf-kappa-b; In-vitro; Ripk1; Tak1; Pathway; Hepatocarcinogenesis; Homeostasis; Senescence; Expression; Biology
Language english
Publication Year 2025
HGF-reported in Year 2025
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 16, Issue: 1, Pages: , Article Number: 1765 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Stem Cell Research (ISF)
Translational Metabolic Oncology (IDC-TMO)
POF-Topic(s) 30204 - Cell Programming and Repair
30203 - Molecular Targets and Therapies
30201 - Metabolic Health
Research field(s) Stem Cell and Neuroscience
Radiation Sciences
Helmholtz Diabetes Center
PSP Element(s) G-500800-001
G-501000-001
G-502502-001
Grants German Cancer Aid (Deutsche Krebshilfe)
Medical faculty of the Heinrich Heine University
German Research Foundation (DFG, German Research Foundation)
Ministry of Culture and Science of the State of North Rhine-Westphalia
German-Research-Foundation
ERC
German Ministry of Health
German Research Foundation
European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program through the ERC Consolidator Grant PhaseControl
I&I future Helmholtz Topic
EOS Flundern grant
MOST grant
BMBF
DKTK (German Cancer Consortium) Strategic Initiative Organoid Platform
European Research Council Grant ERC-AdG-2020 FIBCAN
ARC
French National Research Agency LABEX
Institute Universitaire de France (IUF)
German Cancer Aid
Bavarian Ministry of Economic Affairs, EISglobe
European Union
German Cancer Aid (Max Eder Program, Deutsche Krebshilfe)
German Research Foundation (DFG)
DOI 10.1038/s41467-025-56493-7
WOS ID 001426661700027
Scopus ID 85218446379
PubMed ID 39971907
Erfassungsdatum 2025-05-06
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