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Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma

Author

Listed:
  • Andrea Flesken-Nikitin

    (Cornell University)

  • Coulter Q. Ralston

    (Cornell University
    Cornell University)

  • Dah-Jiun Fu

    (Cornell University)

  • Andrea J. Micheli

    (University Children’s Hospital Zürich)

  • Daryl J. Phuong

    (Cornell University
    Cornell University)

  • Blaine A. Harlan

    (Cornell University)

  • Christopher S. Ashe

    (Cornell University)

  • Amanda P. Armstrong

    (Cornell University)

  • David W. McKellar

    (Cornell University)

  • Sangeeta Ghuwalewala

    (Cornell University)

  • Lora H. Ellenson

    (Memorial Sloan Kettering Cancer Center)

  • John C. Schimenti

    (Cornell University
    Cornell University)

  • Benjamin D. Cosgrove

    (Cornell University)

  • Alexander Yu. Nikitin

    (Cornell University)

Abstract

The distal region of the uterine (Fallopian) tube is commonly associated with high-grade serous carcinoma (HGSC), the predominant and most aggressive form of ovarian or extra-uterine cancer. Specific cell states and lineage dynamics of the adult tubal epithelium (TE) remain insufficiently understood, hindering efforts to determine the cell of origin for HGSC. Here, we report a comprehensive census of cell types and states of the mouse uterine tube. We show that distal TE cells expressing the stem/progenitor cell marker Slc1a3 can differentiate into both secretory (Ovgp1+) and ciliated (Fam183b+) cells. Inactivation of Trp53 and Rb1, whose pathways are commonly altered in HGSC, leads to elimination of targeted Slc1a3+ cells by apoptosis, thereby preventing their malignant transformation. In contrast, pre-ciliated cells (Krt5+, Prom1+, Trp73+) remain cancer-prone and give rise to serous tubal intraepithelial carcinomas and overt HGSC. These findings identify transitional pre-ciliated cells as a cancer-prone cell state and point to pre-ciliation mechanisms as diagnostic and therapeutic targets.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52984-1
    DOI: 10.1038/s41467-024-52984-1
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    References listed on IDEAS

    as
    1. Rui Song & Peter Walentek & Nicole Sponer & Alexander Klimke & Joon Sub Lee & Gary Dixon & Richard Harland & Ying Wan & Polina Lishko & Muriel Lize & Michael Kessel & Lin He, 2014. "miR-34/449 miRNAs are required for motile ciliogenesis by repressing cp110," Nature, Nature, vol. 510(7503), pages 115-120, June.
    2. 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.
    3. Junyue Cao & Malte Spielmann & Xiaojie Qiu & Xingfan Huang & Daniel M. Ibrahim & Andrew J. Hill & Fan Zhang & Stefan Mundlos & Lena Christiansen & Frank J. Steemers & Cole Trapnell & Jay Shendure, 2019. "The single-cell transcriptional landscape of mammalian organogenesis," Nature, Nature, vol. 566(7745), pages 496-502, February.
    4. Andrea Flesken-Nikitin & Chang-Il Hwang & Chieh-Yang Cheng & Tatyana V. Michurina & Grigori Enikolopov & Alexander Yu. Nikitin, 2013. "Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche," Nature, Nature, vol. 495(7440), pages 241-245, March.
    5. Dah-Jiun Fu & Lianghai Wang & Fouad K. Chouairi & Ian M. Rose & Danysh A. Abetov & Andrew D. Miller & Robert J. Yamulla & John C. Schimenti & Andrea Flesken-Nikitin & Alexander Yu. Nikitin, 2020. "Gastric squamous-columnar junction contains a large pool of cancer-prone immature osteopontin responsive Lgr5−CD44+ cells," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
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