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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)\u2013proficient (Trp53\u2212\/\u2212;Ccne1OE;Akt2OE;KrasOE), HR-deficient (Trp53\u2212\/\u2212;Brca1\u2212\/\u2212;MycOE), and unclassified (Trp53\u2212\/\u2212;Pten\u2212\/\u2212;Nf1\u2212\/\u2212) organoids revealed differences in in vitro properties (proliferation, differentiation, and \u201csecretome\u201d), 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\u2013dependent responses in Trp53\u2212\/\u2212;Ccne1OE;Akt2OE;Kras HGSC; in contrast, Trp53\u2212\/\u2212;Pten\u2212\/\u2212;Nf1\u2212\/\u2212 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                    <jats:p>This article is highlighted in the In This Issue feature, p. 211<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-20-0455","type":"journal-article","created":{"date-parts":[[2020,11,6]],"date-time":"2020-11-06T14:40:11Z","timestamp":1604673611000},"page":"362-383","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":93,"title":["Genetically Defined, Syngeneic Organoid Platform for Developing Combination Therapies for Ovarian Cancer"],"prefix":"10.1158","volume":"11","author":[{"given":"Shuang","family":"Zhang","sequence":"first","affiliation":[{"name":"1Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, NYU Langone Health, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3840-5583","authenticated-orcid":false,"given":"Sonia","family":"Iyer","sequence":"additional","affiliation":[{"name":"2Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology (MIT) Ludwig Center for Molecular Oncology and MIT Department of Biology, Cambridge, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Ran","sequence":"additional","affiliation":[{"name":"1Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, NYU Langone Health, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Dolgalev","sequence":"additional","affiliation":[{"name":"1Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, NYU Langone Health, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengqing","family":"Gu","sequence":"additional","affiliation":[{"name":"3Department of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wei","sequence":"additional","affiliation":[{"name":"1Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, NYU Langone Health, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8183-6085","authenticated-orcid":false,"given":"Connor J.R.","family":"Foster","sequence":"additional","affiliation":[{"name":"1Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, NYU Langone Health, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia A.","family":"Loomis","sequence":"additional","affiliation":[{"name":"1Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, NYU Langone Health, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narciso","family":"Olvera","sequence":"additional","affiliation":[{"name":"1Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, NYU Langone Health, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanny","family":"Dao","sequence":"additional","affiliation":[{"name":"1Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, NYU Langone Health, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1038-8232","authenticated-orcid":false,"given":"Douglas A.","family":"Levine","sequence":"additional","affiliation":[{"name":"1Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, NYU Langone Health, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Weinberg","sequence":"additional","affiliation":[{"name":"2Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology (MIT) Ludwig Center for Molecular Oncology and MIT Department of Biology, Cambridge, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin G.","family":"Neel","sequence":"additional","affiliation":[{"name":"1Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, NYU Langone Health, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1086","published-online":{"date-parts":[[2021,2,2]]},"reference":[{"key":"2022060622504161900_bib1","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.smim.2016.01.001","article-title":"Combining targeted therapy with immunotherapy. 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