1. Genetically Defined, Syngeneic Organoid Platform for Developing Combination Therapies for Ovarian Cancer
- Author
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Wei Wei, Connor Foster, Benjamin G. Neel, Douglas A. Levine, Narciso Olvera, Fanny Dao, Robert A. Weinberg, Shengqing Gu, Shuang Zhang, Sonia Iyer, Hao Ran, Igor Dolgalev, and Cynthia Loomis
- Subjects
0301 basic medicine ,Chemokine ,endocrine system diseases ,medicine.medical_treatment ,Mice, Transgenic ,Biology ,medicine.disease_cause ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Tumor Microenvironment ,medicine ,Organoid ,Animals ,Fallopian Tube Neoplasms ,Humans ,CRISPR ,Ovarian Neoplasms ,Immunotherapy ,medicine.disease ,Cystadenocarcinoma, Serous ,3. Good health ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,Disease Models, Animal ,Serous fluid ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Female ,KRAS ,Ovarian cancer - 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
- Published
- 2021