{"doi":"10.7554/elife.101299.1.sa0","title":"Reviewer #3 (Public review): The context-dependent epigenetic and organogenesis programs determine 3D vs. 2D cellular fitness of MYC-driven murine liver cancer cells","abstract":"3D cellular-specific epigenetic and transcriptomic reprogramming is critical to organogenesis and tumorigenesis. Here we dissect the distinct cell fitness in 2D (normoxia vs. chronic hypoxia) vs 3D (normoxia) culture conditions for a MYC-driven murine liver cancer model. We identify over 600 shared essential genes and additional context-specific fitness genes and pathways. Knockout of the VHL-HIF1 pathway results in incompatible fitness defects under normoxia vs. 1% oxygen or 3D culture conditions. Moreover, deletion of each of the mitochondrial respiratory electron transport chain complex has distinct fitness outcomes. Notably, multicellular organogenesis signaling pathways including TGFb-SMAD specifically constrict the uncontrolled cell proliferation in 3D while inactivation of epigenetic modifiers (Bcor, Kmt2d, Mettl3 and Mettl14) has opposite outcomes in 2D vs. 3D. We further identify a 3Ddependent synthetic lethality with partial loss of Prmt5 due to a reduction of Mtap expression resulting from 3D-specific epigenetic reprogramming. Our study highlights unique epigenetic, metabolic and organogenesis signaling dependencies under different cellular settings.","journal":null,"year":2025,"id":559970,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9422,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1341255,"name":"Shivendra Singh","orcid":null,"position":1,"is_corresponding":false},{"id":1336443,"name":"Brennan Wells","orcid":"0009-0006-4698-4801","position":2,"is_corresponding":false},{"id":381373,"name":"Qiong Wu","orcid":"0000-0002-6063-0800","position":3,"is_corresponding":false},{"id":55234,"name":"Hongjian Jin","orcid":"0000-0003-3833-7170","position":4,"is_corresponding":false},{"id":1462145,"name":"Laura Janke","orcid":null,"position":5,"is_corresponding":false},{"id":258822,"name":"Shibiao Wan","orcid":"0000-0003-0661-2684","position":6,"is_corresponding":false},{"id":1034384,"name":"Jacob Steele","orcid":"0000-0001-9924-2226","position":7,"is_corresponding":false},{"id":1462146,"name":"Jon Connelly","orcid":null,"position":8,"is_corresponding":false},{"id":254370,"name":"Andrew Murphy","orcid":"0000-0001-7039-7777","position":9,"is_corresponding":false},{"id":232998,"name":"Ruoning Wang","orcid":"0000-0001-9798-8032","position":10,"is_corresponding":false},{"id":1462147,"name":"Andrew Davidoff","orcid":null,"position":11,"is_corresponding":false},{"id":1164934,"name":"Margaret Ashcroft","orcid":null,"position":12,"is_corresponding":false},{"id":1462148,"name":"Shondra Pruett-Miller","orcid":null,"position":13,"is_corresponding":false},{"id":121395,"name":"Jun Yang","orcid":null,"position":14,"is_corresponding":false},{"id":297494,"name":"Jie Fang","orcid":"0000-0002-0793-9323","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:55:39.010633Z","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":[]}