Genetically Defined, Syngeneic Organoid Platform for Developing Combination Therapies for 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 01, 2021
- Source ID
- 10.1158/2159-8290.cd-20-0455
Entities
People
- Benjamin G. Neel
- Connor J R Foster
- Cynthia A. Loomis
- Douglas A Levine
- Fanny Dao
- Hao Ran
- Igor Dolgalev
- Narciso Olvera
- Robert Weinberg
- Shengqing Gu
- Shuang Zhang
- Sonia Iyer
- Wei Wei
Organizations
- Canadian Institutes of Health Research
- Harvard University
- Honorable Tina Brozman Foundation
- Massachusetts Institute of Technology
- National Institutes of Health
- New York University
- V Foundation for Cancer Research