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Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
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Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma

Mitsuteru Natsuizaka1,2,3,4, Kelly A Whelan1,2,3, Shingo Kagawa1,2,3,5

  • 1Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Nature Communications
|November 25, 2017
PubMed

Insights

Notch1 activation, coupled with transforming growth factor-beta (TGF-β), drives squamous cell carcinoma (SCC) initiation by promoting epithelial-mesenchymal transition (EMT) and generating tumor-initiating cells. This oncogenic role of Notch1 predicts poor prognosis in esophageal SCC.

Area of Science:

  • Oncology
  • Cell Biology
  • Epithelial Biology

Background:

  • Notch1 and Notch3 signaling regulate epithelial differentiation.
  • Notch receptors can act as tumor suppressors or oncogenes in squamous cell carcinomas (SCCs).
  • The role of Notch1 in SCC initiation and progression remains complex.

Purpose of the Study:

  • To investigate the interplay between Notch1, epithelial-mesenchymal transition (EMT), and transforming growth factor-beta (TGF-β) in SCC.
  • To elucidate the mechanism by which Notch1 promotes SCC tumor initiation.
  • To determine the prognostic significance of Notch1 activation in esophageal SCC.

Main Methods:

  • Analysis of Notch1 activation and its correlation with EMT markers.
  • Investigating the role of TGF-β in regulating Notch3 and Notch1-mediated EMT.
  • Assessing Notch1 expression at the invasive tumor front and its prognostic value in esophageal SCC.

Main Results:

  • TGF-β represses Notch3 via ZEB1, limiting terminal differentiation.
  • TGF-β induces Notch1-mediated EMT, generating CD44-high tumor-initiating cells.
  • Notch1 activation at the invasive front of esophageal SCC correlates with poor prognosis.

Conclusions:

  • Notch1 activation and EMT are coupled and promoted by TGF-β in the tumor microenvironment to drive SCC initiation.
  • Notch1 acts as an oncogene in SCC by generating tumor-initiating cells and promoting invasion.
  • Notch1 activation is a potential biomarker for poor prognosis in esophageal SCC.

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