Both fallopian tube and ovarian surface epithelium are cells-of-origin for high-grade serous ovarian carcinoma

Nat Commun. 2019 Nov 26;10(1):5367. doi: 10.1038/s41467-019-13116-2.


The cell-of-origin of high grade serous ovarian carcinoma (HGSOC) remains controversial, with fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) both considered candidates. Here, by using genetically engineered mouse models and organoids, we assessed the tumor-forming properties of FTE and OSE harboring the same oncogenic abnormalities. Combined RB family inactivation and Tp53 mutation in Pax8 + FTE caused Serous Tubal Intraepithelial Carcinoma (STIC), which metastasized rapidly to the ovarian surface. These events were recapitulated by orthotopic injection of mutant FTE organoids. Engineering the same genetic lesions into Lgr5 + OSE or OSE-derived organoids also caused metastatic HGSOC, although with longer latency and lower penetrance. FTE- and OSE-derived tumors had distinct transcriptomes, and comparative transcriptomics and genomics suggest that human HGSOC arises from both cell types. Finally, FTE- and OSE-derived organoids exhibited differential chemosensitivity. Our results comport with a dualistic origin for HGSOC and suggest that the cell-of-origin might influence therapeutic response.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cystadenocarcinoma, Serous / drug therapy
  • Cystadenocarcinoma, Serous / genetics
  • Cystadenocarcinoma, Serous / pathology*
  • Epithelial Cells / pathology
  • Epithelium
  • Fallopian Tube Neoplasms / genetics
  • Fallopian Tube Neoplasms / pathology
  • Fallopian Tubes / pathology*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Mice, Nude
  • Mice, Transgenic
  • Mutation
  • Organoids / drug effects
  • Organoids / pathology
  • Organoids / transplantation
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology*
  • Ovary / pathology*
  • PAX8 Transcription Factor / genetics
  • Receptors, G-Protein-Coupled / genetics
  • Tumor Suppressor Protein p53 / genetics


  • Lgr5 protein, mouse
  • PAX8 Transcription Factor
  • Pax8 protein, mouse
  • Receptors, G-Protein-Coupled
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53