{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T18:00:27Z","timestamp":1776276027103,"version":"3.50.1"},"reference-count":70,"publisher":"American Association for Cancer Research (AACR)","issue":"12","license":[{"start":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T00:00:00Z","timestamp":1642464000000},"content-version":"vor","delay-in-days":183,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["DFG SA 1374\/4-3"],"award-info":[{"award-number":["DFG SA 1374\/4-3"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["SFB 1321 Project-ID 329628492"],"award-info":[{"award-number":["SFB 1321 Project-ID 329628492"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"name":"European Research Council","award":["ERC CoG No. 648521"],"award-info":[{"award-number":["ERC CoG No. 648521"]}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                    <jats:p>This article is highlighted in the In This Issue feature, p. 2945<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-21-0209","type":"journal-article","created":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T04:25:11Z","timestamp":1626668711000},"page":"3158-3177","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Genetic Screens Identify a Context-Specific PI3K\/p27Kip1 Node Driving Extrahepatic Biliary Cancer"],"prefix":"10.1158","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9269-2582","authenticated-orcid":false,"given":"Chiara","family":"Falcomat\u00e0","sequence":"first","affiliation":[{"name":"1Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer 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