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@ARTICLE{Schneider:298979,
      author       = {A. T. Schneider and C. Koppe and E. Crouchet and A.
                      Papargyriou and M. T. Singer and V. Büttner and L. Keysberg
                      and M. Szydlowska$^*$ and F. Jühling and J. Moehlin and
                      M.-C. Chen and V. Leone$^*$ and S. Mueller and T. Neuß and
                      M. Castoldi and M. Lesina and F. Bergmann and T. Hackert and
                      K. Steiger and W. T. Knoefel and A. Zaufel and J. N. Kather
                      and I. Esposito and M. M. Gaida and A. Ghallab and J. G.
                      Hengstler and H. Einwächter and K. Unger and H. Algül and
                      N. Gassler and R. M. Schmid and R. Rad and T. F. Baumert and
                      M. Reichert$^*$ and M. Heikenwälder$^*$ and V. Kondylis and
                      M. Vucur and T. Luedde},
      title        = {{A} decision point between transdifferentiation and
                      programmed cell death priming controls {KRAS}-dependent
                      pancreatic cancer development.},
      journal      = {Nature Communications},
      volume       = {16},
      number       = {1},
      issn         = {2041-1723},
      address      = {[London]},
      publisher    = {Springer Nature},
      reportid     = {DKFZ-2025-00399},
      pages        = {1765},
      year         = {2025},
      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.},
      keywords     = {Animals / Proto-Oncogene Proteins p21(ras): genetics /
                      Proto-Oncogene Proteins p21(ras): metabolism / MAP Kinase
                      Kinase Kinases: metabolism / MAP Kinase Kinase Kinases:
                      genetics / Pancreatic Neoplasms: pathology / Pancreatic
                      Neoplasms: genetics / Pancreatic Neoplasms: metabolism /
                      Carcinoma, Pancreatic Ductal: pathology / Carcinoma,
                      Pancreatic Ductal: genetics / Carcinoma, Pancreatic Ductal:
                      metabolism / Humans / Cell Transdifferentiation / Mice /
                      Mice, Transgenic / Necroptosis / Apoptosis: genetics /
                      Receptor-Interacting Protein Serine-Threonine Kinases:
                      metabolism / Receptor-Interacting Protein Serine-Threonine
                      Kinases: genetics / Organoids: metabolism / Metaplasia /
                      Acinar Cells: metabolism / Acinar Cells: pathology / Acinar
                      Cells: drug effects / MAP kinase kinase kinase 7 (NLM
                      Chemicals) / Proto-Oncogene Proteins p21(ras) (NLM
                      Chemicals) / MAP Kinase Kinase Kinases (NLM Chemicals) /
                      Receptor-Interacting Protein Serine-Threonine Kinases (NLM
                      Chemicals) / Hras protein, mouse (NLM Chemicals) / KRAS
                      protein, human (NLM Chemicals) / Ripk1 protein, mouse (NLM
                      Chemicals)},
      cin          = {D440 / MU01},
      ddc          = {500},
      cid          = {I:(DE-He78)D440-20160331 / I:(DE-He78)MU01-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39971907},
      doi          = {10.1038/s41467-025-56493-7},
      url          = {https://inrepo02.dkfz.de/record/298979},
}