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; Tom Luedde

doi:10.1038/s41467-025-56493-7

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. KnoefelAlex 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, Tom Luedde

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	1765
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-56493-7
State	Published - Dec 2025

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Schneider, A. T., Koppe, C., Crouchet, E., Papargyriou, A., Singer, M. T., Büttner, V., Keysberg, L., 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., ... Luedde, T. (2025). A decision point between transdifferentiation and programmed cell death priming controls KRAS-dependent pancreatic cancer development. Nature Communications, 16(1), Article 1765. https://doi.org/10.1038/s41467-025-56493-7

@article{109f873fbaae4b49a7f10a2362bfefa7,

title = "A decision point between transdifferentiation and programmed cell death priming controls KRAS-dependent pancreatic cancer development",

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.",

author = "Schneider, {Anne T.} and Christiane Koppe and Emilie Crouchet and Aristeidis Papargyriou and Singer, {Michael T.} and Veronika B{\"u}ttner and Leonie Keysberg and Marta Szydlowska and Frank J{\"u}hling and Julien Moehlin and Chen, {Min Chun} and Valentina Leone and Sebastian Mueller and Thorsten Neu{\ss} and Mirco Castoldi and Marina Lesina and Frank Bergmann and Thilo Hackert and Katja Steiger and Knoefel, {Wolfram T.} and Alex Zaufel and Kather, {Jakob N.} and Irene Esposito and Gaida, {Matthias M.} and Ahmed Ghallab and Hengstler, {Jan G.} and Henrik Einw{\"a}chter and Kristian Unger and Hana Alg{\"u}l and Nikolaus Gassler and Schmid, {Roland M.} and Roland Rad and Baumert, {Thomas F.} and Maximilian Reichert and Mathias Heikenwalder and Vangelis Kondylis and Mihael Vucur and Tom Luedde",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1038/s41467-025-56493-7",

language = "English",

volume = "16",

journal = "Nature Communications",

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Schneider, AT, Koppe, C, Crouchet, E, Papargyriou, A, Singer, MT, Büttner, V, Keysberg, L, Szydlowska, M, Jühling, F, Moehlin, J, Chen, MC, Leone, V, Mueller, S, Neuß, T, Castoldi, M, Lesina, M, Bergmann, F, Hackert, T, Steiger, K, Knoefel, WT, Zaufel, A, Kather, JN, Esposito, I, Gaida, MM, Ghallab, A, Hengstler, JG, Einwächter, H, Unger, K, Algül, H, Gassler, N, Schmid, RM, Rad, R, Baumert, TF, Reichert, M, Heikenwalder, M, Kondylis, V, Vucur, M & Luedde, T 2025, 'A decision point between transdifferentiation and programmed cell death priming controls KRAS-dependent pancreatic cancer development', Nature Communications, vol. 16, no. 1, 1765. https://doi.org/10.1038/s41467-025-56493-7

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

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.

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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 -

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

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