Genetically Defined, Syngeneic Organoid Platform for Developing Combination Therapies for Ovarian Cancer
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Updated: Dec 1, 2025
Ovarian Cancer Patient-Derived Organoid Models for Pre-Clinical Drug Testing
Published on: September 15, 2023
Shuang Zhang1, Sonia Iyer2, Hao Ran1
1Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, NYU Langone Health, New York, New York.
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 ), HR-deficient (Trp53 ), and unclassified (Trp53 ) 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 HGSC; in contrast, Trp53 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.
Insights
Researchers developed new mouse models of high-grade serous tubo-ovarian cancer (HGSC) using organoids. These models help evaluate therapies and identified a combination treatment effective for specific HGSC subtypes.
Area of Science:
- Oncology
- Genetics
- Immunology
Background:
- Genetically defined, immunocompetent models are crucial for evaluating cancer therapies.
- High-grade serous tubo-ovarian cancer (HGSC) lacks adequate models for testing treatments.
Purpose of the Study:
- To engineer novel HGSC models using mouse fallopian tube organoids.
- To analyze the biological and therapeutic responses of these models based on genetic profiles.
Main Methods:
- Engineered mouse fallopian tube epithelial organoids using lentiviral gene transduction and CRISPR/Cas9 mutagenesis.
- Generated homologous recombination (HR)-proficient and HR-deficient HGSC models.
- Assessed in vitro properties, copy-number aberrations, tumorigenicity, chemosensitivity, and immune microenvironments.
Main Results:
- Organoid models recapitulated patient HGSC mutational combinations.
- Genotype-dependent differences observed in proliferation, secretome, and tumorigenicity.
- Developed a chemotherapy/immunotherapy regimen showing durable responses in specific HGSC models.
- Identified genotype-dependent similarities between mouse and human HGSC models.
Conclusions:
- Genetically informed organoid models offer a platform for evaluating HGSC biology and therapeutics.
- The study identified a potential effective treatment for CCNE1-amplified HGSC.
- These models can accelerate the development of targeted and immune therapies for HGSC.
