{"doi":"10.1101/2020.12.03.410993","title":"NOTCH-YAP1/TEAD-DNMT1 axis regulates hepatocyte reprogramming into intrahepatic cholangiocarcinoma","abstract":"ABSTRACT Intrahepatic cholangiocarcinoma (ICC), a disease of poor prognosis, has increased in incidence. It is challenging to treat due to intra- and inter-tumoral heterogeneity, which in part is attributed to diverse cellular origin. Indeed, co-expression of AKT and NICD in hepatocytes (HCs) yielded ICC, with similarity to proliferative, Notch-activated, and stem cell-like subclasses of clinical ICC. NICD regulated SOX9 and YAP1 during ICC development. Yap1 deletion or TEAD inhibition impaired HC-to-biliary epithelial cell (BEC) reprogramming and ICC proliferation; Sox9 loss repressed tumor growth; and Yap1-Sox9 combined loss abolished ICC development in AKT-NICD model. DNMT1 was discovered as a novel downstream effector of YAP1-TEAD complex that directed HC-to-BEC/ICC fate-switch. DNMT1 loss prevented Notch-dependent HC-to-ICC development, and DNMT1 re-expression restored ICC development following TEAD repression. Coexpression of DNMT1 with AKT was sufficient to induce hepatic tumor development including ICC. Thus, we have identified a novel NOTCH-YAP1/TEAD-DNMT1 axis essential for HC-driven ICC development. SIGNIFICANCE We evaluated the clinical relevance of hepatocyte-driven ICC model and revealed critical but distinct roles of YAP1 and SOX9 in AKT-NICD-driven hepatocyte-derived ICC. We also identified NOTCH-YAP1/TEAD-DNMT1 axis as a critical driver for hepatocyte-to-ICC reprogramming, which might have biological and therapeutic implications in ICC subsets.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":124219,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9524,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":561892,"name":"Laura Molina","orcid":"0000-0002-3750-6561","position":1,"is_corresponding":false},{"id":328401,"name":"Junyan Tao","orcid":"0000-0002-5249-970X","position":2,"is_corresponding":false},{"id":279404,"name":"Silvia Liu","orcid":"0000-0002-1840-9520","position":3,"is_corresponding":false},{"id":568637,"name":"Mohammed Hassan","orcid":"0000-0003-2981-3542","position":4,"is_corresponding":false},{"id":369006,"name":"Sucha Singh","orcid":"0000-0002-9131-1423","position":5,"is_corresponding":false},{"id":562515,"name":"Minakshi Poddar","orcid":null,"position":6,"is_corresponding":false},{"id":460848,"name":"Aaron Bell","orcid":"0000-0001-6648-0834","position":7,"is_corresponding":false},{"id":231499,"name":"Daniela Sia","orcid":"0000-0002-9000-611X","position":8,"is_corresponding":false},{"id":568638,"name":"Michael Oertel","orcid":"0000-0002-2786-7013","position":9,"is_corresponding":false},{"id":276859,"name":"Reben Raeman","orcid":"0000-0002-3914-1797","position":10,"is_corresponding":false},{"id":369010,"name":"Kari Nejak‐Bowen","orcid":"0000-0001-6051-5338","position":11,"is_corresponding":false},{"id":242167,"name":"Aatur D. Singhi","orcid":"0000-0003-3930-7096","position":12,"is_corresponding":false},{"id":329210,"name":"Jianhua Luo","orcid":"0000-0002-3189-4225","position":13,"is_corresponding":false},{"id":277667,"name":"Satdarshan P. Monga","orcid":"0000-0002-8437-3378","position":14,"is_corresponding":false},{"id":277666,"name":"Sungjin Ko","orcid":"0000-0002-6079-5939","position":15,"is_corresponding":false},{"id":561896,"name":"Shikai Hu","orcid":"0000-0002-0817-991X","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-18T23:15:07.789881Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}