Node Driving Extrahepatic Biliary Cancer Article Swipe

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Chiara Falcomatà , Stefanie Bärthel , Angelika Ulrich , Sandra Diersch , Christian Veltkamp , Lena Rad , Fabio Boniolo , Myriam Solar , Katja Steiger , Barbara Seidler , Magdalena Żukowska , Joanna Madej , Mingsong Wang , Rupert Öllinger , Roman Maresch , Maxim Barenboim , Stefan Eser , Markus Tschurtschenthaler , Arianeb Mehrabi , Stéphanie Roessler , Benjamin Goeppert , Alexander Kind , Angelika Schnieke , María S. Robles , Allan Bradley , Roland M. Schmid , Marc Schmidt-Supprian , Maximilian Reichert , Wilko Weichert , Owen J. Sansom , Jennifer P. Morton , Roland Rad , Günter Schneider , Dieter Saur ·

YOU? · · 2023 · Open Access · · DOI: https://doi.org/10.1158/2159-8290.c.6549328.v1

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 PIK3CA^H1047R but refractory to oncogenic Kras^G12D. 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 p27^Kip1 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 p27^Kip1 permits Kras^G12D-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 p27^Kip1 function are critical determinants for context-specific ECC formation.This article is highlighted in the In This Issue feature, p. 2945

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Kras

Synoeca Septentrionalis

Concepts

KRAS PTEN Cancer research Context (archaeology) Cancer Carcinogenesis Biology PI3K/AKT/mTOR pathway Pancreatic Intraepithelial Neoplasia Genetics Colorectal cancer Signal transduction Paleontology

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Type: preprint
Language: en
Landing Page: https://doi.org/10.1158/2159-8290.c.6549328.v1
OA Status: gold
Related Works: 10
OpenAlex ID: https://openalex.org/W4362546273

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DOI: https://doi.org/10.1158/2159-8290.c.6549328.v1

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Title: Data from Genetic Screens Identify a Context-Specific PI3K/p27<sup>Kip1</sup> Node Driving Extrahepatic Biliary Cancer

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Type: preprint

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Language: en

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Publication year: 2023

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Publication date: 2023-04-03

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Authors: Chiara Falcomatà, Stefanie Bärthel, Angelika Ulrich, Sandra Diersch, Christian Veltkamp, Lena Rad, Fabio Boniolo, Myriam Solar, Katja Steiger, Barbara Seidler, Magdalena Żukowska, Joanna Madej, Mingsong Wang, Rupert Öllinger, Roman Maresch, Maxim Barenboim, Stefan Eser, Markus Tschurtschenthaler, Arianeb Mehrabi, Stéphanie Roessler, Benjamin Goeppert, Alexander Kind, Angelika Schnieke, María S. Robles, Allan Bradley, Roland M. Schmid, Marc Schmidt-Supprian, Maximilian Reichert, Wilko Weichert, Owen J. Sansom, Jennifer P. Morton, Roland Rad, Günter Schneider, Dieter Saur

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Landing page: https://doi.org/10.1158/2159-8290.c.6549328.v1

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OA status: gold

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Concepts: KRAS, PTEN, Cancer research, Context (archaeology), Cancer, Carcinogenesis, Biology, PI3K/AKT/mTOR pathway, Pancreatic Intraepithelial Neoplasia, Genetics, Colorectal cancer, Signal transduction, Paleontology

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