TY  - JOUR
AU  - Schneider, Anne T
AU  - Koppe, Christiane
AU  - Crouchet, Emilie
AU  - Papargyriou, Aristeidis
AU  - Singer, Michael T
AU  - Büttner, Veronika
AU  - Keysberg, Leonie
AU  - Szydlowska, Marta
AU  - Jühling, Frank
AU  - Moehlin, Julien
AU  - Chen, Min-Chun
AU  - Leone, Valentina
AU  - Mueller, Sebastian
AU  - Neuß, Thorsten
AU  - Castoldi, Mirco
AU  - Lesina, Marina
AU  - Bergmann, Frank
AU  - Hackert, Thilo
AU  - Steiger, Katja
AU  - Knoefel, Wolfram T
AU  - Zaufel, Alex
AU  - Kather, Jakob N
AU  - Esposito, Irene
AU  - Gaida, Matthias M
AU  - Ghallab, Ahmed
AU  - Hengstler, Jan G
AU  - Einwächter, Henrik
AU  - Unger, Kristian
AU  - Algül, Hana
AU  - Gassler, Nikolaus
AU  - Schmid, Roland M
AU  - Rad, Roland
AU  - Baumert, Thomas F
AU  - Reichert, Maximilian
AU  - Heikenwälder, Mathias
AU  - Kondylis, Vangelis
AU  - Vucur, Mihael
AU  - Luedde, Tom
TI  - A decision point between transdifferentiation and programmed cell death priming controls KRAS-dependent pancreatic cancer development.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-00399
SP  - 1765
PY  - 2025
AB  - 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.
KW  - Animals
KW  - Proto-Oncogene Proteins p21(ras): genetics
KW  - Proto-Oncogene Proteins p21(ras): metabolism
KW  - MAP Kinase Kinase Kinases: metabolism
KW  - MAP Kinase Kinase Kinases: genetics
KW  - Pancreatic Neoplasms: pathology
KW  - Pancreatic Neoplasms: genetics
KW  - Pancreatic Neoplasms: metabolism
KW  - Carcinoma, Pancreatic Ductal: pathology
KW  - Carcinoma, Pancreatic Ductal: genetics
KW  - Carcinoma, Pancreatic Ductal: metabolism
KW  - Humans
KW  - Cell Transdifferentiation
KW  - Mice
KW  - Mice, Transgenic
KW  - Necroptosis
KW  - Apoptosis: genetics
KW  - Receptor-Interacting Protein Serine-Threonine Kinases: metabolism
KW  - Receptor-Interacting Protein Serine-Threonine Kinases: genetics
KW  - Organoids: metabolism
KW  - Metaplasia
KW  - Acinar Cells: metabolism
KW  - Acinar Cells: pathology
KW  - Acinar Cells: drug effects
KW  - MAP kinase kinase kinase 7 (NLM Chemicals)
KW  - Proto-Oncogene Proteins p21(ras) (NLM Chemicals)
KW  - MAP Kinase Kinase Kinases (NLM Chemicals)
KW  - Receptor-Interacting Protein Serine-Threonine Kinases (NLM Chemicals)
KW  - Hras protein, mouse (NLM Chemicals)
KW  - KRAS protein, human (NLM Chemicals)
KW  - Ripk1 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39971907
DO  - DOI:10.1038/s41467-025-56493-7
UR  - https://inrepo02.dkfz.de/record/298979
ER  -