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Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma

Author

Listed:
  • Mitsuteru Natsuizaka

    (University of Pennsylvania
    Abramson Cancer Center
    University of Pennsylvania Perelman School of Medicine
    Hokkaido University Graduate School of Medicine, Sapporo)

  • Kelly A. Whelan

    (University of Pennsylvania
    Abramson Cancer Center
    University of Pennsylvania Perelman School of Medicine)

  • Shingo Kagawa

    (University of Pennsylvania
    Abramson Cancer Center
    University of Pennsylvania Perelman School of Medicine
    Chiba University Graduate School of Medicine)

  • Koji Tanaka

    (University of Pennsylvania
    Abramson Cancer Center
    University of Pennsylvania Perelman School of Medicine
    Osaka University Graduate School of Medicine)

  • Veronique Giroux

    (University of Pennsylvania
    Abramson Cancer Center
    University of Pennsylvania Perelman School of Medicine)

  • Prasanna M. Chandramouleeswaran

    (University of Pennsylvania
    Abramson Cancer Center
    University of Pennsylvania Perelman School of Medicine)

  • Apple Long

    (University of Pennsylvania
    Abramson Cancer Center
    University of Pennsylvania Perelman School of Medicine)

  • Varun Sahu

    (Abramson Cancer Center
    University of Pennsylvania Perelman School of Medicine
    University of Pennsylvania)

  • Douglas S. Darling

    (University of Louisville)

  • Jianwen Que

    (Columbia University)

  • Yizeng Yang

    (University of Pennsylvania
    Abramson Cancer Center
    University of Pennsylvania Perelman School of Medicine)

  • Jonathan P. Katz

    (University of Pennsylvania
    Abramson Cancer Center
    University of Pennsylvania Perelman School of Medicine)

  • E. Paul Wileyto

    (Abramson Cancer Center
    University of Pennsylvania Perelman School of Medicine
    University of Pennsylvania)

  • Devraj Basu

    (Abramson Cancer Center
    University of Pennsylvania Perelman School of Medicine
    University of Pennsylvania)

  • Yoshiaki Kita

    (Kagoshima University Graduate School of Medical and Dental Sciences)

  • Shoji Natsugoe

    (Kagoshima University Graduate School of Medical and Dental Sciences)

  • Seiji Naganuma

    (Kochi Medical School)

  • Andres J. Klein-Szanto

    (Fox Chase Cancer Center)

  • J. Alan Diehl

    (Medical University of South Carolina)

  • Adam J. Bass

    (Harvard Medical School)

  • Kwok-Kin Wong

    (Harvard Medical School
    New York University)

  • Anil K. Rustgi

    (University of Pennsylvania Perelman School of Medicine)

  • Hiroshi Nakagawa

    (University of Pennsylvania Perelman School of Medicine)

Abstract

Notch1 transactivates Notch3 to drive terminal differentiation in stratified squamous epithelia. Notch1 and other Notch receptor paralogs cooperate to act as a tumor suppressor in squamous cell carcinomas (SCCs). However, Notch1 can be stochastically activated to promote carcinogenesis in murine models of SCC. Activated form of Notch1 promotes xenograft tumor growth when expressed ectopically. Here, we demonstrate that Notch1 activation and epithelial–mesenchymal transition (EMT) are coupled to promote SCC tumor initiation in concert with transforming growth factor (TGF)-β present in the tumor microenvironment. We find that TGFβ activates the transcription factor ZEB1 to repress Notch3, thereby limiting terminal differentiation. Concurrently, TGFβ drives Notch1-mediated EMT to generate tumor initiating cells characterized by high CD44 expression. Moreover, Notch1 is activated in a small subset of SCC cells at the invasive tumor front and predicts for poor prognosis of esophageal SCC, shedding light upon the tumor promoting oncogenic aspect of Notch1 in SCC.

Suggested Citation

  • Mitsuteru Natsuizaka & Kelly A. Whelan & Shingo Kagawa & Koji Tanaka & Veronique Giroux & Prasanna M. Chandramouleeswaran & Apple Long & Varun Sahu & Douglas S. Darling & Jianwen Que & Yizeng Yang & J, 2017. "Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma," Nature Communications, Nature, vol. 8(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01500-9
    DOI: 10.1038/s41467-017-01500-9
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    Cited by:

    1. Haidi Huang & Yu Jiang & Jiangying Liu & Dan Luo & Jianghong Yuan & Rongzi Mu & Xiang Yu & Donglei Sun & Jihong Lin & Qiyue Chen & Xinjing Li & Ming Jiang & Jianming Xu & Bo Chu & Chengqian Yin & Lei , 2024. "Jag1/2 maintain esophageal homeostasis and suppress foregut tumorigenesis by restricting the basal progenitor cell pool," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Mohammad Faujul Kabir & Adam L. Karami & Ricardo Cruz-Acuña & Alena Klochkova & Reshu Saxena & Anbin Mu & Mary Grace Murray & Jasmine Cruz & Annie D. Fuller & Margarette H. Clevenger & Kumaraswamy Nai, 2022. "Single cell transcriptomic analysis reveals cellular diversity of murine esophageal epithelium," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Bartosz Mucha & Shuo Qie & Sagar Bajpai & Vincenzo Tarallo & J. Nathaniel Diehl & Frank Tedeschi & Gao Zhou & Zhaofeng Gao & Samuel Flashner & Andres J. Klein-Szanto & Hanina Hibshoosh & Shimonosono M, 2022. "Tumor suppressor mediated ubiquitylation of hnRNPK is a barrier to oncogenic translation," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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