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EMT-induced stemness and tumorigenicity are fueled by the EGFR/Ras pathway

Dominic Chih-Cheng Voon1, Huajing Wang, Jason Kin Wai Koo

  • 1The Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.

Plos One
|August 17, 2013
PubMed

Insights

Epithelial-Mesenchymal Transition (EMT) grants differentiated cells stem-like, tumorigenic traits. The EGFR/Ras pathway specifically drives this plasticity and tumor initiation in gastric cells, independent of EMT.

Area of Science:

  • Gastroenterology
  • Cancer Biology
  • Cellular Biology

Background:

  • Differentiated epithelial cells can gain stem cell-like and tumorigenic properties after Epithelial-Mesenchymal Transition (EMT).
  • The specific signaling pathways driving this EMT-induced tumorigenesis remain incompletely understood.
  • Runx3 (-/-) p53 (-/-) murine gastric epithelial (GIF-14) cells exhibit EMT-induced plasticity, marked by Hmga2 and Lgr5 expression.

Purpose of the Study:

  • To investigate the signaling pathways involved in EMT-induced stemness and tumorigenicity in gastric epithelial cells.
  • To determine the role of the EGFR/Ras pathway in promoting plasticity and tumor-initiating cell generation following EMT.

Main Methods:

  • Induction of EMT in GIF-14 cells using TGF-β1.
  • Analysis of gene expression changes, including EGFR, Ras, Hmga2, and Lgr5.
  • Assessment of cellular plasticity and tumorigenicity through sphere formation and soft agar assays.
  • Investigating the effects of co-treatment with TGF-β1 and EGF, and expression of exogenous KRas.

Main Results:

  • Concurrent activation of an EGFR/Ras gene expression signature was observed during TGF-β1-induced EMT in GIF-14 cells.
  • EGFR induction correlated with delayed EGF sensitization, while co-treatment with TGF-β1 and EGF or KRas expression increased Hmga2/Lgr5, sphere initiation, and colony formation.
  • Acquisition of plasticity and tumorigenicity occurred without a corresponding increase in EMT, indicating an uncoupling of these processes.
  • The EGFR/Ras pathway was found to be essential for maintaining gastric stem cells in vitro and in vivo.

Conclusions:

  • The EGFR/Ras pathway specifically promotes stemness and tumorigenicity in EMT-altered gastric cells, independent of EMT.
  • This pathway is involved in the generation and progression of EMT-induced tumor-initiating cells.
  • Decoupling EMT from plasticity induction highlights distinct signaling mechanisms in tumorigenesis.

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