{"doi":"10.1101/gad.348295.121","title":"ASCL1 represses a SOX9 <sup>+</sup> neural crest stem-like state in small cell lung cancer","abstract":"ASCL1 is a neuroendocrine lineage-specific oncogenic driver of small cell lung cancer (SCLC), highly expressed in a significant fraction of tumors. However, ∼25% of human SCLC are ASCL1-low and associated with low neuroendocrine fate and high MYC expression. Using genetically engineered mouse models (GEMMs), we show that alterations in Rb1/Trp53/Myc in the mouse lung induce an ASCL1 + state of SCLC in multiple cells of origin. Genetic depletion of ASCL1 in MYC-driven SCLC dramatically inhibits tumor initiation and progression to the NEUROD1 + subtype of SCLC. Surprisingly, ASCL1 loss promotes a SOX9 + mesenchymal/neural crest stem-like state and the emergence of osteosarcoma and chondroid tumors, whose propensity is impacted by cell of origin. ASCL1 is critical for expression of key lineage-related transcription factors NKX2-1, FOXA2, and INSM1 and represses genes involved in the Hippo/Wnt/Notch developmental pathways in vivo. Importantly, ASCL1 represses a SOX9/RUNX1/RUNX2 program in vivo and SOX9 expression in human SCLC cells, suggesting a conserved function for ASCL1. Together, in a MYC-driven SCLC model, ASCL1 promotes neuroendocrine fate and represses the emergence of a SOX9 + nonendodermal stem-like fate that resembles neural crest.","journal":"Genes & Development","year":2021,"id":212849,"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":78,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9498,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":302443,"name":"Abbie S. Ireland","orcid":"0000-0002-4178-7239","position":1,"is_corresponding":false},{"id":576968,"name":"David W. Kastner","orcid":"0000-0002-7766-4249","position":2,"is_corresponding":false},{"id":576969,"name":"Sarah M. Groves","orcid":"0000-0002-3122-2605","position":3,"is_corresponding":false},{"id":680898,"name":"Kyle B. Spainhower","orcid":null,"position":4,"is_corresponding":false},{"id":338880,"name":"Karine Pozo","orcid":"0000-0002-2749-9353","position":5,"is_corresponding":false},{"id":803969,"name":"Demetra P. Kelenis","orcid":"0000-0003-1718-6633","position":6,"is_corresponding":false},{"id":577896,"name":"Christopher P. Whitney","orcid":null,"position":7,"is_corresponding":false},{"id":154830,"name":"Matthew R. Guthrie","orcid":null,"position":8,"is_corresponding":false},{"id":251323,"name":"Sarah J. Wait","orcid":"0000-0001-5660-2391","position":9,"is_corresponding":false},{"id":577897,"name":"Danny Soltero","orcid":null,"position":10,"is_corresponding":false},{"id":577898,"name":"Benjamin L. Witt","orcid":null,"position":11,"is_corresponding":false},{"id":251321,"name":"Vito Quaranta","orcid":"0000-0001-7491-8672","position":12,"is_corresponding":false},{"id":251311,"name":"Jane E. Johnson","orcid":"0000-0002-8605-2746","position":13,"is_corresponding":false},{"id":6196,"name":"Trudy G. Oliver","orcid":"0000-0003-2082-2397","position":14,"is_corresponding":false},{"id":357500,"name":"Rachelle R. Olsen","orcid":null,"position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":null,"created_at":"2026-07-18T23:52:31.378994Z","pmid":"34016693","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":[]}