A decision point between transdifferentiation and programmed cell death priming controls KRAS-dependent pancreatic cancer development
Abstract
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.
Article Details
Authors (38)
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 Algul
Nikolaus Gaßler
Roland M. Schmid
Roland Rad
Thomas F. Baumert
Maximilian Reichert
Mathias Heikenwälder
Vangelis Kondylis
Mihael Vucur
Tom Luedde