| First Author | Falcomatà C | Year | 2021 |
| Journal | Cancer Discov | PubMed ID | 34282029 |
| Mgi Jnum | J:316040 | Mgi Id | MGI:6832732 |
| Doi | 10.1158/2159-8290.CD-21-0209 | Citation | Falcomata C, et al. (2021) Genetic Screens Identify a Context-Specific PI3K/p27(Kip1) Node Driving Extrahepatic Biliary Cancer. Cancer Discov |
| abstractText | 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. |
