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

Author

Listed:
  • Shuang Zhang

    (NYU Langone Health)

  • Igor Dolgalev

    (NYU Langone Health)

  • Tao Zhang

    (NYU Langone Health)

  • Hao Ran

    (NYU Langone Health)

  • Douglas A. Levine

    (NYU Langone Health)

  • Benjamin G. Neel

    (NYU Langone Health)

Abstract

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.

Suggested Citation

  • Shuang Zhang & Igor Dolgalev & Tao Zhang & Hao Ran & Douglas A. Levine & Benjamin G. Neel, 2019. "Both fallopian tube and ovarian surface epithelium are cells-of-origin for high-grade serous ovarian carcinoma," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13116-2
    DOI: 10.1038/s41467-019-13116-2
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    Cited by:

    1. Elena Denisenko & Leanne Kock & Adeline Tan & Aaron B. Beasley & Maria Beilin & Matthew E. Jones & Rui Hou & Dáithí Ó Muirí & Sanela Bilic & G. Raj K. A. Mohan & Stuart Salfinger & Simon Fox & Khaing , 2024. "Spatial transcriptomics reveals discrete tumour microenvironments and autocrine loops within ovarian cancer subclones," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Andrea Flesken-Nikitin & Coulter Q. Ralston & Dah-Jiun Fu & Andrea J. Micheli & Daryl J. Phuong & Blaine A. Harlan & Christopher S. Ashe & Amanda P. Armstrong & David W. McKellar & Sangeeta Ghuwalewal, 2024. "Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Liana Goehring & Sarah Keegan & Sudipta Lahiri & Wenxin Xia & Michael Kong & Judit Jimenez-Sainz & Dipika Gupta & Ronny Drapkin & Ryan B. Jensen & Duncan J. Smith & Eli Rothenberg & David Fenyö & Tony, 2024. "Dormant origin firing promotes head-on transcription-replication conflicts at transcription termination sites in response to BRCA2 deficiency," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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