{"doi":"10.1101/2022.03.27.485965","title":"CRISPR-induced exon skipping of β-catenin reveals tumorigenic mutants driving distinct subtypes of liver cancer","abstract":"Abstract CRISPR/Cas9-driven cancer modeling studies are based on disruption of tumor suppressor genes (TSGs) by small insertions or deletions (indels) that lead to frame-shift mutations. In addition, CRISPR/Cas9 is widely used to define the significance of cancer oncogenes and genetic dependencies in loss-of function studies. However, how CRISPR/Cas9 influences gain-of-function oncogenic mutations is elusive. Here, we demonstrate that single guide RNA targeting exon 3 of β-catenin results in exon skipping and generates gain-of-function isoforms in vivo . CRISPR/Cas9-mediated exon skipping of β-catenin induces liver tumor formation in synergy with YAP S127A in mice. We define two distinct exon skipping-induced tumor subtypes with different histological and transcriptional features. Notably, ectopic expression of two exon-skipped β-catenin transcript isoforms together with YAP S127A phenocopies the two distinct subtypes of liver cancer. Moreover, we identify similar β-catenin exon skipping events in hepatocellular carcinoma (HCC) patients. Collectively, our findings advance our understanding of β-catenin-related tumorigenesis and reveal that CRISPR/Cas9 can be repurposed, in vivo, to study gain-of-function mutations of oncogenes in cancer.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":299926,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"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":0.9483,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":990523,"name":"Junjiayu Yue","orcid":null,"position":1,"is_corresponding":false},{"id":678956,"name":"Ying Jin","orcid":"0000-0003-0070-2048","position":2,"is_corresponding":false},{"id":554178,"name":"Zhikai Wang","orcid":"0000-0002-8565-6011","position":3,"is_corresponding":false},{"id":554179,"name":"Ya Gao","orcid":"0000-0002-9280-4457","position":4,"is_corresponding":false},{"id":103965,"name":"Tobias Janowitz","orcid":"0000-0002-7820-3727","position":5,"is_corresponding":false},{"id":64945,"name":"Hannah V. Meyer","orcid":"0000-0003-4564-0899","position":6,"is_corresponding":false},{"id":64946,"name":"Alper Küçükural","orcid":"0000-0001-9983-394X","position":7,"is_corresponding":false},{"id":228779,"name":"John E. Wilkinson","orcid":"0000-0001-9174-8556","position":8,"is_corresponding":false},{"id":64927,"name":"Deniz M. Özata","orcid":"0000-0001-5215-8684","position":9,"is_corresponding":false},{"id":39709,"name":"Semir Beyaz","orcid":"0000-0003-4730-4012","position":10,"is_corresponding":false},{"id":64925,"name":"Haiwei Mou","orcid":"0000-0002-1710-1882","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:31:49.412501Z","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":[]}