Fiche publication
Date publication
février 2025
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BAUMERT Thomas
,
Dr CROUCHET Emilie
Tous les auteurs :
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
Lien Pubmed
Résumé
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.
Mots clés
Animals, Proto-Oncogene Proteins p21(ras), genetics, MAP Kinase Kinase Kinases, metabolism, Pancreatic Neoplasms, pathology, Carcinoma, Pancreatic Ductal, pathology, Humans, Cell Transdifferentiation, Mice, Mice, Transgenic, Necroptosis, Apoptosis, genetics, Receptor-Interacting Protein Serine-Threonine Kinases, metabolism, Organoids, metabolism, Metaplasia, Acinar Cells, metabolism
Référence
Nat Commun. 2025 02 19;16(1):1765
