Genetic Screens Identify a Context-Specific PI3K/p27Kip1 Node Driving Extrahepatic Biliary Cancer.

Falcomata, Chiara; Barthel, Stefanie; Ulrich, Angelika; Diersch, Sandra; Veltkamp, Christian; Rad, Lena; Boniolo, Fabio; Solar, Myriam; Steiger, Katja; Seidler, Barbara; Zukowska, Magdalena; Madej, Joanna; Wang, Mingsong; Ollinger, Rupert; Maresch, Roman; Barenboim, Maxim; Eser, Stefan; Tschurtschenthaler, Markus; Mehrabi, Arianeb; Roessler, Stephanie; Goeppert, Benjamin; Kind, Alexander; Schnieke, Angelika; Robles, Maria S; Bradley, Allan; Schmid, Roland M; Schmidt-Supprian, Marc; Reichert, Maximilian; Weichert, Wilko; Sansom, Owen J; Morton, Jennifer P; Rad, Roland; Schneider, Gunter; Saur, Dieter     «

Falcomata, Chiara; Barthel, Stefanie; Ulrich, Angelika; Diersch, Sandra; Veltkamp, Christian; Rad, Lena; Boniolo, Fabio; Solar, Myriam; Steiger, Katja; Seidler, Barbara; Zukowska, Magdalena; Madej, Joanna; Wang, Mingsong; Ollinger, Rupert; Maresch, Roman; Barenboim, Maxim; Eser, Stefan; Tschurtschenthaler, Markus; Mehrabi, Arianeb; Roessler, Stephanie; Goeppert, Benjamin; Kind, Alexander; Schnieke, Angelika; Robles, Maria S; Bradley, Allan; Schmid, Roland M; Schmidt-Supprian, Marc; Reichert, Max...     »

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. This article is highlighted in the In This Issue feature, p. 2945.      «

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...     »