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Genetic screens identify a context-specific PI3K/p27Kip1 node driving extrahepatic biliary cancer

Biliary tract cancer ranks among the most lethal human malignancies, representing an unmet clinical need. Its abysmal prognosis is tied to an increasing incidence and a fundamental lack of mechanistic knowledge regarding the molecular basis of the disease. Here, we show that the Pdx1-positive extrah...

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Main Authors: Falcomatà, Chiara (Author) , Bärthel, Stefanie (Author) , Ulrich, Angelika (Author) , Diersch, Sandra (Author) , Veltkamp, Christian (Author) , Rad, Lena (Author) , Boniolo, Fabio (Author) , Solar, Myriam (Author) , Steiger, Katja (Author) , Seidler, Barbara (Author) , Zukowska, Magdalena (Author) , Madej, Joanna (Author) , Wang, Mingsong (Author) , Öllinger, Rupert (Author) , Maresch, Roman (Author) , Barenboim, Maxim (Author) , Eser, Stefan (Author) , Tschurtschenthaler, Markus (Author) , Mehrabi, Arianeb (Author) , Rössler, Stephanie (Author) , Goeppert, Benjamin (Author) , Kind, Alexander (Author) , Schnieke, Angelika (Author) , Robles, Maria S. (Author) , Bradley, Allan (Author) , Schmid, Roland M. (Author) , Schmidt-Supprian, Marc (Author) , Reichert, Maximilian (Author) , Weichert, Wilko (Author) , Sansom, Owen J. (Author) , Morton, Jennifer P. (Author) , Rad, Roland (Author) , Schneider, Günter (Author) , Saur, Dieter (Author)
Format: Article (Journal)
Language:English
Published: July 19, 2021
In: Cancer discovery
Year: 2021, Volume: 11, Issue: 12, Pages: 3158-3177
ISSN:2159-8290
DOI:10.1158/2159-8290.CD-21-0209
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1158/2159-8290.CD-21-0209
Verlag, lizenzpflichtig, Volltext: https://cancerdiscovery.aacrjournals.org/content/11/12/3158
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Author Notes:Chiara Falcomatà, Stefanie Bärthel, Angelika Ulrich, Sandra Diersch, Christian Veltkamp, Lena Rad, Fabio Boniolo, Myriam Solar, Katja Steiger, Barbara Seidler, Magdalena Zukowska, Joanna Madej, Mingsong Wang, Rupert Öllinger, Roman Maresch, Maxim Barenboim, Stefan Eser, Markus Tschurtschenthaler, Arianeb Mehrabi, Stephanie Roessler, Benjamin Goeppert, Alexander Kind, Angelika Schnieke, Maria S. Robles, Allan Bradley, Roland M. Schmid, Marc Schmidt-Supprian, Maximilian Reichert, Wilko Weichert, Owen J. Sansom, Jennifer P. Morton, Roland Rad, Günter Schneider, and Dieter Saur

MARC

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520 |a Biliary tract cancer ranks among the most lethal human malignancies, representing an unmet clinical need. Its abysmal prognosis is tied to an increasing incidence and a fundamental lack of mechanistic knowledge regarding the molecular basis of the disease. Here, we show that the Pdx1-positive extrahepatic biliary epithelium is highly susceptible toward transformation by activated PIK3CAH1047R but refractory to oncogenic KrasG12D. Using genome-wide transposon screens and genetic loss-of-function experiments, we discover context-dependent genetic interactions that drive extrahepatic cholangiocarcinoma (ECC) and show that PI3K signaling output strength and repression of the tumor suppressor p27Kip1 are critical context-specific determinants of tumor formation. This contrasts with the pancreas, where oncogenic Kras in concert with p53 loss is a key cancer driver. Notably, inactivation of p27Kip1 permits KrasG12D-driven ECC development. These studies provide a mechanistic link between PI3K signaling, tissue-specific tumor suppressor barriers, and ECC pathogenesis, and present a novel genetic model of autochthonous ECC and genes driving this highly lethal tumor subtype. - Significance: We used the first genetically engineered mouse model for extrahepatic bile duct carcinoma to identify cancer genes by genome-wide transposon-based mutagenesis screening. Thereby, we show that PI3K signaling output strength and p27Kip1 function are critical determinants for context-specific ECC formation. 
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