Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation (original) (raw)

  1. Luika A. Timmerman1,6,
  2. Joaquín Grego-Bessa2,5,6,
  3. Angel Raya3,
  4. Esther Bertrán2,
  5. José María Pérez-Pomares4,
  6. Juan Díez2,
  7. Sergi Aranda2,
  8. Sergio Palomo2,
  9. Frank McCormick1,
  10. Juan Carlos Izpisúa-Belmonte3, and
  11. José Luis de la Pompa2,5,7
  12. 1 University of California Comprehensive Cancer Center, San Francisco, California 94115, USA
  13. 2 Departamento de Oncología Molecular, Institut de Recerca Oncologica (IRO), Hospital Duran i Reynals, Barcelona, Spain
  14. 3 Gene Expression Laboratories, The Salk Institute for Biological Studies, La Jolla, California 92037-1099, USA
  15. 4 Departamento de Biología Animal, Facultad de Ciencias, Universidad de Málaga, 29071 Málaga, Spain

Abstract

Epithelial-to-mesenchymal transition (EMT) is fundamental to both embryogenesis and tumor metastasis. The Notch intercellular signaling pathway regulates cell fate determination throughout metazoan evolution, and overexpression of activating alleles is oncogenic in mammals. Here we demonstrate that Notch activity promotes EMT during both cardiac development and oncogenic transformation via transcriptional induction of the Snail repressor, a potent and evolutionarily conserved mediator of EMT in many tissues and tumor types. In the embryonic heart, Notch functions via lateral induction to promote a selective transforming growth factor-β (TGFβ)-mediated EMT that leads to cellularization of developing cardiac valvular primordia. Embryos that lack Notch signaling elements exhibit severely attenuated cardiac snail expression, abnormal maintenance of intercellular endocardial adhesion complexes, and abortive endocardial EMT in vivo and in vitro. Accordingly, transient ectopic expression of activated Notch1 (N1IC) in zebrafish embryos leads to hypercellular cardiac valves, whereas Notch inhibition prevents valve development. Overexpression of N1IC in immortalized endothelial cells in vitro induces EMT accompanied by oncogenic transformation, with corresponding induction of snail and repression of VE-cadherin expression. Notch is expressed in embryonic regions where EMT occurs, suggesting an intimate and fundamental role for Notch, which may be reactivated during tumor metastasis.

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