{"doi":"10.1158/2159-8290.cd-20-0455","title":"Genetically Defined, Syngeneic Organoid Platform for Developing Combination Therapies for Ovarian Cancer","abstract":"Abstract The paucity of genetically informed, immunocompetent tumor models impedes evaluation of conventional, targeted, and immune therapies. By engineering mouse fallopian tube epithelial organoids using lentiviral gene transduction and/or CRISPR/Cas9 mutagenesis, we generated multiple high-grade serous tubo-ovarian cancer (HGSC) models exhibiting mutational combinations seen in patients with HGSC. Detailed analysis of homologous recombination (HR)–proficient (Trp53−/−;Ccne1OE;Akt2OE;KrasOE), HR-deficient (Trp53−/−;Brca1−/−;MycOE), and unclassified (Trp53−/−;Pten−/−;Nf1−/−) organoids revealed differences in in vitro properties (proliferation, differentiation, and “secretome”), copy-number aberrations, and tumorigenicity. Tumorigenic organoids had variable sensitivity to HGSC chemotherapeutics, and evoked distinct immune microenvironments that could be modulated by neutralizing organoid-produced chemokines/cytokines. These findings enabled development of a chemotherapy/immunotherapy regimen that yielded durable, T cell–dependent responses in Trp53−/−;Ccne1OE;Akt2OE;Kras HGSC; in contrast, Trp53−/−;Pten−/−;Nf1−/− tumors failed to respond. Mouse and human HGSC models showed genotype-dependent similarities in chemosensitivity, secretome, and immune microenvironment. Genotype-informed, syngeneic organoid models could provide a platform for the rapid evaluation of tumor biology and therapeutics. Significance: The lack of genetically informed, diverse, immunocompetent models poses a major barrier to therapeutic development for many malignancies. Using engineered fallopian tube organoids to study the cell-autonomous and cell-nonautonomous effects of specific combinations of mutations found in HGSC, we suggest an effective combination treatment for the currently intractable CCNE1-amplified subgroup. This article is highlighted in the In This Issue feature, p. 211","journal":"Cancer Discovery","year":2020,"id":55720,"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":91,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9416,"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":263323,"name":"Sonia Iyer","orcid":"0000-0003-3840-5583","position":1,"is_corresponding":false},{"id":238055,"name":"Hao Ran","orcid":"0000-0002-7375-3359","position":2,"is_corresponding":false},{"id":238065,"name":"Igor Dolgalev","orcid":"0000-0003-4451-126X","position":3,"is_corresponding":false},{"id":243340,"name":"Shengqing Gu","orcid":"0000-0002-4200-0864","position":4,"is_corresponding":false},{"id":288715,"name":"Wei Wei","orcid":"0000-0001-5929-7409","position":5,"is_corresponding":false},{"id":238054,"name":"Connor Foster","orcid":"0000-0001-8183-6085","position":6,"is_corresponding":false},{"id":75654,"name":"Cynthia A. Loomis","orcid":"0000-0001-8668-1270","position":7,"is_corresponding":false},{"id":290328,"name":"Narciso Olvera","orcid":null,"position":8,"is_corresponding":false},{"id":288716,"name":"Fanny Dao","orcid":"0000-0001-5285-6044","position":9,"is_corresponding":false},{"id":1720,"name":"Douglas A. Levine","orcid":"0000-0003-1038-8232","position":10,"is_corresponding":false},{"id":23828,"name":"Robert A. Weinberg","orcid":"0000-0002-0895-3557","position":11,"is_corresponding":false},{"id":238068,"name":"Benjamin G. Neel","orcid":"0000-0002-9589-585X","position":12,"is_corresponding":false},{"id":288714,"name":"Shuang Zhang","orcid":"0000-0002-6313-0537","position":0,"is_corresponding":true}],"reference_count":115,"raw_metadata":null,"created_at":"2026-07-18T21:05:29.672878Z","pmid":"33158842","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":[]}