TY - JOUR
T1 - A decision point between transdifferentiation and programmed cell death priming controls KRAS-dependent pancreatic cancer development
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 - Heikenwalder, Mathias
AU - Kondylis, Vangelis
AU - Vucur, Mihael
AU - Luedde, Tom
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85218446379&partnerID=8YFLogxK
U2 - 10.1038/s41467-025-56493-7
DO - 10.1038/s41467-025-56493-7
M3 - Article
AN - SCOPUS:85218446379
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1765
ER -
