Dichotomous ovarian cancer-initiating potential of Pax8+ cells revealed by a mouse genetic mosaic model

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...

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Bibliographic Details
Published in:iScience 2023-05, Vol.26 (5), p.106742-106742, Article 106742
Main Authors: Zeng, Jianhao, Alvarez-Yela, Astrid Catalina, Casarez, Eli, Jiang, Ying, Wang, Lixin, Kelly, Brianna E., Jenkins, Taylor, Ke, Eugene, Atkins, Kristen A., Janes, Kevin A., Slack-Davis, Jill K., Zong, Hui
Format: Article
Language:English
Subjects:
Biological sciences
Cancer
Cell biology
Transcriptomics
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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. [Display omitted] •A mouse genetic mosaic model is used for clonal analysis during premalignancy•A rare subset of stem/progenitor-like Pax8+ cells seeds ovarian cancer•Oncogenic mutations promote tumor progression via prolonged clonal expansion•Expanded mutant clones manifest biased differentiation toward Pax8+ fate Biological sciences; Cell biology; Cancer; Transcriptomics
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2023.106742