Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation

TLDR

Epithelial‑to‑mesenchymal transition drives embryogenesis and tumor metastasis, and the Notch signaling pathway, which governs cell fate and is oncogenic when overexpressed, regulates this process. The study shows that Notch activity promotes EMT during cardiac development and oncogenic transformation by inducing the Snail repressor. In the embryonic heart, Notch signals via lateral induction to trigger TGFβ‑mediated EMT that drives cellularization of developing cardiac valvular primordia. Loss of Notch signaling reduces cardiac Snail expression, disrupts endocardial adhesion, and blocks EMT, while ectopic Notch1 activation causes hypercellular valves and induces EMT and oncogenic transformation in endothelial cells, indicating Notch’s essential role in EMT during development and potential reactivation in metastasis.

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.