In vivo modeling of metastatic human high-grade serous ovarian cancer in mice

PLoS Genet. 2020 Jun 4;16(6):e1008808. doi: 10.1371/journal.pgen.1008808. eCollection 2020 Jun.

Abstract

Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most common and deadliest human ovarian cancer type. Mice genetically engineered to harbor Dicer1 and Pten inactivation and mutant p53 robustly replicate the peritoneal metastases of human HGSC with complete penetrance. Arising from the fallopian tube, tumors spread to the ovary and metastasize throughout the pelvic and peritoneal cavities, invariably inducing hemorrhagic ascites. Widespread and abundant peritoneal metastases ultimately cause mouse deaths (100%). Besides the phenotypic and histopathological similarities, mouse HGSCs also display marked chromosomal instability, impaired DNA repair, and chemosensitivity. Faithfully recapitulating the clinical metastases as well as molecular and genomic features of human HGSC, this murine model will be valuable for elucidating the mechanisms underlying the development and progression of metastatic ovarian cancer and also for evaluating potential therapies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Chromosomal Instability
  • Cystadenocarcinoma, Serous / drug therapy
  • Cystadenocarcinoma, Serous / genetics*
  • Cystadenocarcinoma, Serous / secondary
  • DEAD-box RNA Helicases / genetics
  • DNA Repair
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics
  • Drug Screening Assays, Antitumor / methods
  • Feasibility Studies
  • Female
  • Humans
  • Mice
  • Mice, Knockout
  • Mutation
  • Neoplasm Grading
  • Neoplasm Metastasis / genetics
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology*
  • PTEN Phosphohydrolase / genetics
  • Peritoneal Neoplasms / drug therapy
  • Peritoneal Neoplasms / genetics*
  • Peritoneal Neoplasms / secondary
  • Primary Cell Culture
  • Ribonuclease III / genetics
  • Tumor Suppressor Protein p53 / genetics

Substances

  • Antineoplastic Agents
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Dicer1 protein, mouse
  • Ribonuclease III
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • DEAD-box RNA Helicases