Dichotomous ovarian cancer-initiating potential of Pax8+ cells revealed by a mouse genetic mosaic model
Jianhao Zeng,
Astrid Catalina Alvarez-Yela,
Eli Casarez,
Ying Jiang,
Lixin Wang,
Brianna E. Kelly,
Taylor Jenkins,
Eugene Ke,
Kristen A. Atkins,
Kevin A. Janes,
Jill K. Slack-Davis,
Hui Zong
Affiliations
Jianhao Zeng
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
Astrid Catalina Alvarez-Yela
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA
Eli Casarez
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
Ying Jiang
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
Lixin Wang
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA
Brianna E. Kelly
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
Taylor Jenkins
Department of Pathology, University of Virginia Health System, Charlottesville, VA 22908, USA
Eugene Ke
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA
Kristen A. Atkins
Department of Pathology, University of Virginia Health System, Charlottesville, VA 22908, USA; University of Virginia Cancer Center, University of Virginia Health System, Charlottesville, VA 22903, USA
Kevin A. Janes
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA; University of Virginia Cancer Center, University of Virginia Health System, Charlottesville, VA 22903, USA
Jill K. Slack-Davis
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA; University of Virginia Cancer Center, University of Virginia Health System, Charlottesville, VA 22903, USA; Corresponding author
Hui Zong
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA; University of Virginia Cancer Center, University of Virginia Health System, Charlottesville, VA 22903, USA; Corresponding author
Summary: Different cellular compartments within a tissue present distinct cancer-initiating capacities. Current approaches to dissect such heterogeneity require cell-type-specific genetic tools based on a well-understood lineage hierarchy, which are lacking for many tissues. Here, we circumvented this hurdle and revealed the dichotomous capacity of fallopian tube Pax8+ cells in initiating ovarian cancer, utilizing a mouse genetic system that stochastically generates rare GFP-labeled mutant cells. Through clonal analysis and spatial profiling, we determined that only clones founded by rare, stem/progenitor-like Pax8+ cells can expand on acquiring oncogenic mutations whereas vast majority of clones stall immediately. Furthermore, expanded mutant clones undergo further attrition: many turn quiescent shortly after the initial expansion, whereas others sustain proliferation and manifest a bias toward Pax8+ fate, underlying early pathogenesis. Our study showcases the power of genetic mosaic system-based clonal analysis for revealing cellular heterogeneity of cancer-initiating capacity in tissues with limited prior knowledge of lineage hierarchy.
