Related Experiment Video
Updated: Dec 1, 2025
Ovarian Cancer Patient-Derived Organoid Models for Pre-Clinical Drug Testing
Published on: September 15, 2023
Genetically Defined, Syngeneic Organoid Platform for Developing Combination Therapies for Ovarian Cancer
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.
