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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)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Nf-kappa-b; In-vitro; Ripk1; Tak1; Pathway; Hepatocarcinogenesis; Homeostasis; Senescence; Expression; Biology
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Zeitschrift Nature Communications
Quellenangaben Band: 16, Heft: 1, Seiten: , Artikelnummer: 1765 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Stem Cell Research (ISF)
Translational Metabolic Oncology (IDC-TMO)
Förderungen 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)