Assessing the origin of high-grade serous ovarian cancer using CRISPR-modification of mouse organoids

Kadi Lõhmussaar, Oded Kopper, Jeroen Korving, Harry Begthel, Celien P H Vreuls, Johan H van Es, Hans Clevers

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

High-grade serous ovarian cancer (HG-SOC)-often referred to as a "silent killer"-is the most lethal gynecological malignancy. The fallopian tube (murine oviduct) and ovarian surface epithelium (OSE) are considered the main candidate tissues of origin of this cancer. However, the relative contribution of each tissue to HG-SOC is not yet clear. Here, we establish organoid-based tumor progression models of HG-SOC from murine oviductal and OSE tissues. We use CRISPR-Cas9 genome editing to introduce mutations into genes commonly found mutated in HG-SOC, such as Trp53, Brca1, Nf1 and Pten. Our results support the dual origin hypothesis of HG-SOC, as we demonstrate that both epithelia can give rise to ovarian tumors with high-grade pathology. However, the mutated oviductal organoids expand much faster in vitro and more readily form malignant tumors upon transplantation. Furthermore, in vitro drug testing reveals distinct lineage-dependent sensitivities to the common drugs used to treat HG-SOC in patients.

Original languageEnglish
Pages (from-to)2660
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 27 May 2020

Keywords

  • Animals
  • Antineoplastic Agents/pharmacology
  • BRCA1 Protein/genetics
  • CRISPR-Associated Protein 9
  • CRISPR-Cas Systems/genetics
  • Epithelium/pathology
  • Fallopian Tubes/pathology
  • Female
  • Gene Editing/methods
  • Mice
  • Mutation
  • Neurofibromatosis 1/genetics
  • Organ Culture Techniques/methods
  • Organoids/drug effects
  • Ovarian Neoplasms/drug therapy
  • Ovary/pathology
  • PTEN Phosphohydrolase/genetics
  • Tumor Suppressor Protein p53/genetics

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